Lower dosage strength imiquimod formulations and short dosing regimens for treating genital and perianal warts

ABSTRACT

Pharmaceutical formulations and methods for the topical or transdermal delivery of 1isobutyl-1H-imidazo[4,5-c]-quinolin-4-amine or 1-(2-methylpropyl)-1H-imidazo[4,5 c]quinolin-4-amine, i.e., imiquimod, to treat genital/perianal warts with shorter durations of therapy than currently prescribed for the commercially available for Aldara® 5% imiquimod cream, as now approved by the U.S. Food &amp; Drug Administration (“FDA”), are disclosed and described. More specifically, lower dosage strength imiquimod formulations to deliver an efficacious dose of imiquimod for treating genital/perianal warts with an acceptable safety profile and dosing regimens that are shorter and more convenient for patient use than the dosing regimen currently approved by the U.S. Food &amp; Drug Administration (“FDA”) for Aldara® 5% imiquimod cream to treat genital/perianal warts are also disclosed and described.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.14/796,296 filed Jul. 10, 2015, which is a continuation of U.S. patentapplication Ser. No. 14/091,965 filed Nov. 27, 2013, which is acontinuation of U.S. patent application Ser. No. 13/559,473 filed Jul.26, 2012, which is a continuation of U.S. patent application Ser. No.12/771,076 filed Apr. 3, 2010; and which claims priority to U.S.Provisional Patent Application No. 61/341,721 filed Apr. 1, 2010, U.S.Provisional Patent Application No. 61/341,476 filed Mar. 30, 2010, andU.S. Provisional Patent Application No. 61/225,202 filed Jul. 13, 2009,the teachings of which are hereby incorporated by reference in theirentireties for all purposes.

FIELD OF THE INVENTION

The present invention relates to pharmaceutical formulations and methodsfor the topical or transdermal delivery of1-isobutyl-1H-imidazo[4,5-c]-quinolin-4-amine, also known as (a.k.a.)1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine, a.k.a. imiquimod,to treat genital and perianal warts with shorter durations of therapy,than currently prescribed for the commercially available Aldara® 5%imiquimod cream, as now approved by the U.S. Food & Drug Administration(“FDA”). More specifically, the present invention is directed to lowerdosage strength imiquimod formulations to deliver an efficacious dosefor treating genital and perianal warts with an acceptable safetyprofile, but with a dosing regimen that is shorter and more convenientfor patient use than the dosing regimen currently approved by the FDAfor Aldara® 5% imiquimod cream.

BACKGROUND OF THE INVENTION

External Genital Warts (EGW), or condylomata acuminate, are caused byinfection with human papilloma virus (HPV), the most common sexuallytransmitted virus in the Western world (Lyttle 1994, Mayeaux 1995, Shah1990). Approximately 1% of the sexually active population between 15 and49 years of age in the US is estimated to have EGW (Koutsky 1988,Koutsky 1997). Most EGWs are associated with HPV types 6 and 11 (Phelps1995).

In 1997, imiquimod 5% cream (Aldara®) was approved for the treatment ofEGW and perianal warts. Imiquimod, an immune response modifier thatstimulates the innate and adaptive immune response, has beendemonstrated to be an effective and safe treatment for EGWs. Stimulationof the immune response has been shown to decrease HPV viral load(Kreuter 2006) and may decrease the recurrence rate of visible warts,although observed rates after treatments do vary.

Imiquimod, however, has no direct antiviral activity in cell culture. Astudy in 22 patients with genital/perianal warts comparing Aldara® 5%imiquimod cream and vehicle shows that Aldara® 5% imiquimod creaminduces mRNA encoding cytokines including interferon-α at the treatmentsite. In addition, HPVL1 mRNA and HPV DNA are significantly decreasedfollowing treatment. However, the clinical relevance of these findingsis unknown.

Specific antiviral therapy for the treatment of EGW is lacking, but drugand other therapies have been used. Ablative treatment modalitiesinclude procedures such as surgical excision, laser therapy, andcryotherapy. Other approaches include topical treatments, such as aceticacid, podophylline, podophyllotoxin, and 5-fluorouracil, which arecytodestructive, and sinecatechins, whose mechanism of action isunknown. Each of these therapies has disadvantages such as inconvenientregimens, pain or burning associated with the therapy, scarring,itching, or high recurrence rates.

Aldara® 5% imiquimod cream is approved for the treatment of externalgenital and perianal warts (condylomata acuminata) in individuals 12years old and above (Aldara® Package Insert). The approved dosingregimen is 3 times per week, for up to 16 weeks of treatment.

The compound characterized as1-isobutyl-1H-imidazo[4,5-c]-quinolin-4-amine or1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine, and known asimiquimod, is disclosed in U.S. Pat. No. 4,689,338 and described thereinas an antiviral agent and as an interferon inducer. A variety offormulations for topical administration of imiquimod are also describedtherein. This U.S. Pat. No. 4,689,338 is incorporated herein byreference in its entirety.

U.S. Pat. No. 4,751,087 discloses the use of a combination of ethyloleate and glyceryl monolaurate as a skin penetration enhancer fornitroglycerin, with all three components being contained in the adhesivelayer of a transdermal patch; this U.S. patent is incorporated herein byreference in its entirety.

U.S. Pat. No. 4,411,893 discloses the use ofN,N-dimethyldodecylamine-N-oxide as a skin penetration enhancer inaqueous systems; this U.S. patent is incorporated herein by reference inits entirety.

U.S. Pat. No. 4,722,941 discloses readily absorbable pharmaceuticalcompositions that comprise a pharmacologically active agent distributedin a vehicle comprising an absorption-enhancing amount of at least onefatty acid containing 6 to 12 carbon atoms and optionally a fatty acidmonoglyceride. Such compositions are said to be particularly useful forincreasing the absorption of pharmacologically active bases; this U.S.patent is incorporated herein by reference in its entirety.

U.S. Pat. No. 4,746,515 discloses a method of using glyceryl monolaurateto enhance the transdermal flux of a transdermally deliverable drugthrough intact skin; this U.S. patent is incorporated herein byreference in its entirety.

U.S. Pat. Nos. 5,238,944, 7,038,051, 6,693,113, 6,894,060, 7,655,672,U.S. Patent Publication No. 2009/0093514 A1, U.S. Patent Publication No.2007/0123558, U.S. Patent Publication No. 2004/087614, U.S. PatentPublication No. 2002/147210, PCT Publication No. WO2008082381 and PCTPublication No. WO2008US53522 disclose topical formulations and/ortopical and transdermal delivery systems containing1-isobutyl-1H-imidazo[4,5-c]-quinolin-4-amine or1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine; each of thesepatents and patent publications are incorporated herein by reference intheir entireties.

Currently, the FDA has approved a 5% imiquimod cream, commerciallyavailable under the brand name Aldara®, to treat certain dermal andmucosal associated conditions, such as (1) the topical treatment ofclinically typical, nonhyperkeratotic actinic keratosis (AK) on the faceor scalp in immunocompetent adults, (2) topical treatment ofbiopsy-confirmed, primary superficial basal cell carcinoma (sBCC) inimmunocompetent adults, and (3) the topical treatment of externalgenital and perianal warts/condyloma acuminate (hereinafter,individually or jointly “EGWs”) in patients 12 years or older.

Aldara® is the brand name for an FDA-approved 5% imiquimod cream, whichis an immune response modifier. Each gram of the Aldara® 5% imiquimodcream contains 50 mg of imiquimod in an off-white oil-in-water vanishingcream base consisting of isostearic acid, cetyl alcohol, stearylalcohol, white petrolatum, polysorbate 60, sorbitan monostearate,glycerin, xanthan gum, purified water, benzyl alcohol, methylparaben,and propylparaben. The Aldara® 5% imiquimod cream is packaged insingle-use packets or sachets, each containing 250 mg of cream,equivalent to 12.5 mg of imiquimod.

Chemically, imiquimod, as indicated above, is known as1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine or1-isobutyl-1H-imidazo[4,5-c]-quinolin-4-amine. Imiquimod has a molecularformula of C₁₄H₁₆N₄ and a molecular weight of 240.3. The chemicalstructural formula for imiquimod is as follows:

Notwithstanding FDA approval, Aldara® 5% imiquimod cream treatment forEGWs is not without limitation, including an unsimplified and lengthydosing regimen (administration three times per week until totalclearance of EGWs is achieved, or up to 16 weeks). According to theLDA-approved label for Aldara® 5% imiquimod cream, the median time tocomplete wart clearance is 10 weeks. The eccentric dosing schedule isnot easy to remember, which could lead to reduced compliance withresulting reduced efficacy. If applied too thickly or generously,Aldara® 5% imiquimod cream can cause site or local skin reactions, suchas erosions or ulcerations, causing pain or dysfunction (e.g., of theforeskin or urethra). In addition, efficacy of treatment with Aldara® 5%imiquimod cream may be limited, especially in men, in patients withlongstanding or recurrent disease, or for treatment of keratinized areas(e.g., inguinal). In some cases, a rest period from scheduled dosingwith Aldara® 5% imiquimod cream may be needed, and consultation orreevaluation by healthcare provider may also be required. Othersymptoms, such as perianal itching or systemic effects such as flu-likesymptoms, may also occur in some cases after treatment with Aldara® 5%imiquimod cream.

In view of the above, there is a need for improved EGW topical treatmentthat overcomes the current limitations associated with the currentFDA-approved topical treatment regimen for EGWs, i.e., administrationuntil there is total clearance of the EGWs, for up to 16 weeks, threedays per week, with FDA-approved Aldara® 5% imiquimod cream.

SUMMARY OF THE INVENTION

The present invention addresses the above-mentioned limitationsassociated with the treatment of EGWs with FDA-approved Aldara® 5%imiquimod cream through the discovery of novel and improved imiquimodtreatment regimens of short duration, lower dosage strength imiquimodpharmaceutical formulations, and simplified dosing regimens to treatEGWs.

Generally speaking, the present invention provides for new and improvedsubstantially less-irritating lower dosage strength imiquimodpharmaceutical formulations, which are suitable for daily application inconnection with substantially condensed treatment regimens, for topicaland/or transdermal administration of an effective amount of imiquimod totreat subjects who are diagnosed with external genital and perianalwarts/condyloma acuminate (EGWs). In addition, the present inventionprovides for new and improved EGW treatments, wherein: (1) treatmentperiods of the present invention are substantially shorter in duration,i.e., up to eight weeks and preferably up to six weeks or four weeks,than the current FDA-approved up-to-16-week treatment regimen for EGWstreatment; (2) dosing regimens of the present invention aresubstantially simpler, i.e., one application daily each day for up toeight weeks and preferably up to six weeks or four weeks, than thecurrent dosing regimen, as compared to the once-a-day but only threetimes per week for up to 16 weeks regimen for the current FDA-approvedAldara® 5% imiquimod cream for EGWs treatment; (3) less-irritatingimiquimod pharmaceutical formulations of the present invention areformulated with a lower dosage strength, i.e., between about 1% andabout 4.25% imiquimod, than the current FDA-approved Aldara® 5%imiquimod cream for EGWs treatment; and (4) lower subject incidence ofapplication site reactions is experienced in accordance with the presentinvention, as compared with higher subject incidence of application sitereactions experienced with the current FDA-approved Aldara® 5% imiquimodcream and treatment regimen for EGWs treatment.

In other words, the present invention provides for new and improved EGWstreatments that have short durations of therapies, use lower imiquimoddosage strengths, have simplified daily dosing regimens, and have alower incidence of application site reactions, as compared to treatmentof EGWs with Aldara® 5% imiquimod cream, as currently approved by theFDA.

The present invention thus provides numerous surprising advantages overcurrent FDA-approved Aldara® 5% imiquimod cream therapy for EGWstreatment. For example, the present invention provides for (1) ashortened treatment regimen, i.e., up to about 8 weeks, or preferably upto about 6 weeks and preferably up to about 4 weeks, (2) a simplifieddosing regimen, i.e., once daily on each day of the treatment period,(3) low systemic imiquimod blood levels even though the dosing frequencyis increased, and (4) a lower subject incidence of application sitereactions during the topical treatment regimen of EGWs, than currentlyassociated with FDA-approved Aldara® 5% imiquimod cream therapy.

Thus, the present invention overcomes certain of the limitationsassociated with the treatment of EGWs with FDA-approved Aldara® 5%imiquimod cream and addresses current medical needs for (1) a shortertreatment period, (2) a more intuitive dosing regimen (daily dosing vs.thrice weekly dosing for Aldara® 5% imiquimod cream) and (3) less or alower incidence of application site reactions.

The less-irritating lower dosage strength imiquimod pharmaceuticalformulations of the present invention may comprise:

1. a lower dosage strength of1-isobutyl-1H-imidazo[4,5-c]-quinolin-4-amine or1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine (imiquimod) fordelivering an effective amount of imiquimod; and

2. a pharmaceutically acceptable vehicle for imiquimod, which vehiclecomprises a fatty acid, such as isostearic acid, palmitic acid, stearicacid, linoleic acid, unrefined oleic acid, refined oleic acid, such asSuper Refined® oleic acid NF (e.g., a highly purified oleic acid, i.e.,an oleic acid which has low polar purities, such as peroxides, a lowperoxide value and is marketed by CRODA; see e.g., www.crodausa.com) anda combination thereof, in a total amount of about 3 percent to about 45percent by weight based on the total weight of the formulation.

The lower dosage strength imiquimod formulations of the presentinvention, especially those wherein the vehicle comprises an isostearicacid as the fatty acid, are uniquely designed to have physical andchemical stability, solubility, emollient properties and doseproportionate delivery similar to or better than Aldara® 5% imiquimodcream. More specifically, the lower dosage strength imiquimodformulations of the present invention, especially those wherein thevehicle comprises an isostearic acid as the fatty acid, are believed togenerally have similar or improved skin emolliency at the applicationsite and dose proportionate release rates as to both the release ratesof the imiquimod and the total amount of imiquimod released, relative tothe Aldara® 5% imiquimod cream. In other words, the lower dosagestrength imiquimod formulations of the present invention areconcentration influenced and have similar release rates to the Aldara®5% imiquimod cream. Additionally, the greater the amount of imiquimod inthe formulation, the faster and the greater the total amount ofimiquimod is released, evidencing that the amount in and the rate ofrelease from the formulations are imiquimod concentration dependent.Thus, while the lower dose strength imiquimod formulations of thepresent invention deliver different cumulative amounts to the stratumcorneum and epidermis, i.e., local skin delivery, than the Aldara® 5%imiquimod cream, such lower dosage strength imiquimod formulations arebelieved to have a proportional and linear relationship that is similarwith the Aldara® 5% imiquimod cream as to both the rate of imiquimodrelease and the total amount of imiquimod released and delivered locallyto the skin over time, so that the imiquimod concentrations in theformulations of the present invention, the imiquimod release rates andthe amount of imiquimod unabsorbed and delivered to the stratum corneumand epidermis, which has been released from the formulations, aregenerally proportional and linear to the Aldara® 5% imiquimod cream.

In addition, the lower dosage strength imiquimod formulations of thepresent invention, especially those wherein the vehicle comprises anisostearic acid as the fatty acid, are uniquely designed to be stableand fall within the range of the specifications for the commerciallyavailable Aldara® 5% imiquimod cream, such as to viscosity, pH, andstability, including microscopic and macroscopic stability. Morespecifically, the imiquimod present in the lower dosage strengthimiquimod formulations of the present invention, especially thosewherein the vehicle comprises an isostearic acid as the fatty acid,(monograph range: 90 to 110%) and benzyl alcohol (monograph range: 50 to105%) remain within limits at both about 25° C. and about 40° C. overabout a one month period and within limits at both about 25° C. andabout 40° C. over about a six month period. Furthermore, the lowerdosage strength imiquimod formulations of the present invention,especially those wherein the vehicle comprises an isostearic acid as thefatty acid, remain stabile for about six months at about 25° C. andabout 40° C., and also remain stable with respect to macroscopic andmicroscopic appearance, viscosity (monograph range: 2,000 to 35000 cPs)and pH (monograph range 4.0 to 5.5). In addition, the lower dosagestrength imiquimod formulations of the present invention are uniquelydesigned to meet the requirements specified in both United StatesPharmacopeia (“USP”) and the European Pharmacopeia (“EP”) as topreservative efficacy and remain free of degradation products whenstored at about 25° C./60% RH, about 30° C./65% RH and about 40° C./75%RH over about one, about two, about three and about six months andanalyzed at about 318 nm wavelength.

The present invention also contemplates lower dosage strength imiquimodformulations that have unique pharmacokinetic profiles when used, forexample, in connection with the short durations of therapy to treat EGWsin accordance with the present invention. By way of example, a 3.75%imiquimod lower dosage strength formulation of the present invention,when approximately 250 mg of such a formulation (about 9.375 mgimiquimod) or less is applied daily for 21 days to EGWs in thegenital/perianal area with a total wart area of greater than or equal to100 mm², achieves steady state by about Day 7, and provides an in-vivoserum profile selected from one or more of the following:

(a) a Day 21 mean T_(max) of about 9.7 hours with a standard deviation(“SD”) of about 4.0, a median T_(max) of about 12 hours and a geometricmean T_(max) of about 8.3 hours and a coefficient of variation (“CV”) ofabout 41%;

(b) a Day 21 mean C_(max) of about 0.488 ng/ml with a standard deviationof about 0.368, a median C_(max) of about 0.45 and a geometric meanC_(max) of about 0.39 ng/mL and a coefficient of variation of about 75%;

(c) a Day 21 T_(1/2) of from about 6.8 to about 54 hours and preferablya mean T_(1/2), of about 24.1 hours with a standard deviation of about12, a median T_(1/2) of about 22.8 hours and a geometric mean T_(1/2) ofabout 21 hours and a coefficient of variation of about 51%;

(d) a Day 21 AUC₀₋₂₄ of from about 1.9 to about 14 ng-hr/mL andpreferably a mean AUC₀₋₂₄ of about 6.8 ng·hr/mL, with a standarddeviation of about 3.6, a median AUC₀₋₂₄ of about 6.6 ng·hr/mL and ageometric mean AUC₀₋₂₄ of about 5.8 ng-hr/mL and a coefficient ofvariation of about 53%;

(e) a Day 21 λz of from about 0.013 hr⁻¹ to about 0.102 hr⁻¹ andpreferably a mean λz of about 0.037 hr⁻¹ with a standard deviation ofabout 0.02, a median λz of about 0.03 hr⁻¹ and a geometric mean λz ofabout 0.03 hr⁻¹ and a coefficient of variation of about 60%;

(f) a Day 21 C_(min) of from about 0.025 to about 0.47 and preferably amean C_(min) of about 0.158 with an SD of about 0.121, a median C_(min)of about 0.14 and a geometric mean C_(min) of about 0.11 and acoefficient of variation of about 77%;

(g) at Day 14/7 (a ratio of the trough concentration at Day 14 over thetrough concentration at Day 7), a trough concentration geometric meanratio of about 1.13 with a 90% confidence interval (“CI”) within a rangeof between about 0.7 and about 1.7;

(h) at Day 21/14 (a ratio of the trough concentration at Day 21 over thetrough concentration at Day 14), a trough concentration geometric meanratio of about 0.84 with a 90% confidence interval (“CI”) within a rangeof between about 0.5 and about 1.3;

(i) at Day 22/21 (a ratio of the trough concentration at Day 22 over thetrough concentration at Day 21) a trough concentration geometric meanratio of about 1.12 with a 90% confidence interval (“CI”) within a rangeof between about 0.7 and about 1.6;

(j) a mean peak imiquimod serum concentration of about 0.488 ng/mL atDay 21;

(k) a Day 21 RAUC of from about 0.6 to about 7 and preferably a meanRAUC of about 2.2 with a standard deviation of about 1.8, a median RAUCof about 1.8 and a geometric mean RAUC of about 1.7 and a coefficient ofvariation of about 81%;

(l) a Day 21 RC_(max) of from about 0.5 to about 5 and preferably a meanRC_(max) of about 2.3 with a standard deviation of about 1.6, a medianRC_(max) of about 1.7 and a geometric mean RC_(max), of about 1.8 and acoefficient of variation of about 70%;

(m) a Day 21 L λz_(eff) of from about 0.006 hr⁻¹ to about 0.09 hr⁻¹ andpreferably a mean L λz_(eff) of about 0.04 hr-1 with a standarddeviation of about 0.03, a median L λz_(eff) of about 0.03 hr⁻¹ and ageometric mean L λz_(eff) of about 0.03 hr⁻¹ and a coefficient ofvariation of about 69%;

(n) a Day 21 T^(1/2 eff) of from about 8 hr to about 111 hr andpreferably a mean T^(1/2) _(eff) of about 31 hr with a standarddeviation of about 30, a median T^(1/2) _(eff) of about 22 hr and ageometric mean T^(1/2) _(eff) of about 23 hr⁻¹ and a coefficient ofvariation of about 97%;

(o) a Day 21 C_(max) in female patients about 61% higher in femalesubjects than in male subjects (0.676 versus 0.420 ng/mL) and totalsystemic exposure AUC 0-24 8% higher in female subjects than in malesubjects (7.192 versus 6.651 ng-hr/mL) when data is not dose normalized:

(p) a Day 21 C_(max) in female patients about 35% higher than in malesubjects (0.583 versus 0.431 ng/mL) and AUC 0-24 about 6% lower infemale subjects than in male subjects (6.428 versus 6.858 ng-hr/mL) whenusing dose normalization to adjust for differences in dosage andreported without subjects who missed an application of study drug duringthe last week of dosing; and/or

(q) a median T_(max) occurring approximately twice as quickly in femalesubjects (about 6.50 hours) as in male subjects (about 12.0 hours).

In accordance with the present invention, a mean peak serumconcentration is achieved with a 3.75% lower dosage strength imiquimodformulation of Examples 23-26. More specifically, a mean peak serumconcentration of about 0.488 ng/mL is achieved with a 3.75% lower dosagestrength imiquimod formulation of Examples 23-26 after about 9.4 mg ofimiquimod is applied to the affected treatment area each day for up to 8weeks.

Furthermore, this invention provides the following evidence of clinicalefficacy: The wart area decreased by 45% from a mean of 108.3 mm² atbaseline to 43.2 mm² at Day 21, e.g., see Table 145. The P value of<0.0001 for this change from baseline indicated a statisticallysignificant ≤0.050) decrease in wart area after 3 weeks of treatment.

In accordance with the present invention, a mean peak serumconcentration is achieved with a 3.75% lower dosage strength imiquimodformulation of Examples 23-26. More specifically, a mean peak serumconcentration of about 0.488 ng/ml is achieved with a 3.75% lower dosagestrength imiquimod formulation of Examples 23-26 after about 9.4 mg ofimiquimod is applied to the affected treatment area, i.e., the externalgenital/perianal warts, each day until completely cleared or for up toeight weeks.

In addition, the present invention contemplates lower dosage strengthformulations that are pharmaceutically equivalent, therapeuticallyequivalent, bioequivalent and/or interchangeable, regardless of themethod selected to demonstrate equivalents or bioequivalence, such asdermatopharmacokinetic and pharmacokinetic methodologies, microdialysis,in vitro and in vivo methods and/or clinical endpoints. Thus, thepresent invention contemplates lower dosage strength imiquimodformulations that are bioequivalent, pharmaceutically equivalent and/ortherapeutic equivalent, especially, 2.5% and 3.75% lower dosage strengthimiquimod formulations that are bioequivalent, pharmaceuticallyequivalent and/or therapeutically equivalent, when used daily inaccordance with the short durations of therapy of the present inventionto treat EGWs, e.g., used on treatment areas, on a daily basis untilcomplete wart clearance or for up to about eight weeks, six weeks, or upto about 4 weeks, optionally including a rest (no drug application)period.

Thus, the present invention contemplates: (a) pharmaceuticallyequivalent lower dosage strength imiquimod formulations which containthe same amount of imiquimod in the same dosage form; (b) bioequivalentlower dosage strength imiquimod formulations which are chemicallyequivalent and which, when administered to the same individuals in thesame dosage regimens, result in comparable bioavailabilities; (c)therapeutic equivalent lower dosage strength imiquimod formulationswhich, when administered to the same individuals in the same dosageregimens, provide essentially the same efficacy and/or toxicity; and (d)interchangeable lower dosage strength imiquimod formulations of thepresent invention which are pharmaceutically equivalent, bioequivalentand therapeutically equivalent.

By the term “lower dosage strength(s)”, as used herein, it refers to apharmaceutical formulation containing imiquimod in an amount of betweenabout 1.0 percent and about 4.25 percent by weight based on the totalweight of the formulation and preferably a pharmaceutical formulationcontaining imiquimod in an amount of about 2.5% or about 3.75%.

By the term “short duration(s)” of therapy, as used herein, it refers tothe daily topical application of an effective amount of imiquimod to adefined treatment area diagnosed with EGWs for a total on-treatmentperiod of up to about 8 weeks, 6 weeks, or 4 weeks, depending upon whichlower dosage strength imiquimod formulation of the present invention isselected for daily application, and more preferably a total on-treatmentperiod of up to about 8, 6, or 4 weeks to treat EGWs. In addition, the“short durations” of therapy may also include an 8 week examinationperiod (no further treatment) following the treatment period.

As indicated above, when the short durations of therapy are used incombination with the lower dosage strength imiquimod formulations of thepresent invention, it is surprisingly found that (1) simplified dailydosing regimens can be used, (2) the therapy is better tolerated thanstandard therapy with 5% imiquimod (Aldara®), resulting in effectivetreatment with lower dosage strength imiquimod formulations withoutinducing significant local skin reactions or irritation in the treatmentarea or treatment limiting adverse events which could result inpremature therapy termination or significant voluntary rest periods ofseveral days that are generally associated with higher concentrations ofimiquimod therapy. It is also surprisingly found that as much as betweenabout 250 mg of a low dosage strength imiquimod formulation may be usedper application in accordance with the present invention, especiallywhen the short durations of therapy are used in combination with the lowdosage strength imiquimod formulations of the present invention.

Also quite surprisingly, the efficacy achieved by the lower dosagestrength imiquimod formulations when used in either of the shortdurations of therapy, e.g., an up to 8-week treatment regimen, of thepresent invention for treatment of EGWs as to total clearance, partialclearance and a reduction in the number of warts is statisticallysignificant over placebo, e.g., when a 3.75% imiquimod cream is used.

It should be noted that the efficacy P value that is achieved for apercent reduction in the number of warts for a 3.75% lower dosagestrength imiquimod formulation versus a 2.5% lower dosage strengthimiquimod formulation that is utilized in accordance with a treatmentregimen of the present invention is not always statisticallysignificant.

It should be understood that the short durations of therapy and lowerdosage strength imiquimod formulations of the present invention arebelieved to be optimized to treat EGWs. By “optimized”, it is meantherein that the short durations of therapy and lower dosage strengthimiquimod formulations of the present invention are designed to achieveefficacy, stability and release rates profiles that are at leastessentially equivalent to and linear with Aldara® 5% imiquimod cream,respectively, but with an improved acceptable safety profile. In thiscontext, it should be appreciated that the primary efficacy variableused in the studies of the short durations of therapy and lower dosagestrength imiquimod formulations of the present invention (completeclearance of all warts, both Baseline and newly emerged, in all assessedanatomic areas) was very conservative (see, e.g., Example 24), whencompared to reported studies of Aldara® 5% imiquimod cream.

By the term “acceptable safety profile”, it is meant herein to mean thattreatment of EGWs with a short duration of therapy and a lower dosagestrength imiquimod formulation in accordance with the present invention,does not cause treatment limiting side effects or rest periods in anappreciable number of subjects undergoing therapy for EGWs to a levelthat causes premature termination of treatment. The term “acceptablesafety profile” also refers to treatment of EGWs with a short durationof therapy and a lower dosage strength imiquimod formulation of thepresent invention with a lower subject incidence of application sitereactions as compared with treatment of EGWs with Aldara® 5% imiquimodcream.

The salient elements of a pharmaceutical formulation according to thepresent invention are (a) imiquimod and (b) a fatty acid, e.g.,isostearic, palmitic, stearic, linoleic, unrefined oleic acid or refinedoleic acid, such as Super Refined® oleic acid NF (e.g., a highlypurified oleic acid, i.e., an oleic acid which has low polar impurities,such as peroxides, a low peroxide value and is marketed by CRODA; seee.g., www.crodausa.com) and mixtures thereof A pharmaceuticalformulation of the invention can be in any form known to the art,including semi-solid dosage forms, such as a cream, an ointment, a foam,a gel, a lotion or a pressure-sensitive adhesive composition, each formcontaining the necessary elements in particular amounts and furthercontaining various additional elements.

A cream of the invention contains an effective amount of imiquimod, suchas between about greater than 1 percent and about 4.25 percent by weightof imiquimod, based on the total weight of the cream; about 5 percent toabout 30 percent by weight of fatty acid, based on the total weight ofthe cream; and optional ingredients such as emollients, emulsifiers,thickeners, and/or preservatives.

An ointment of the invention contains an ointment base in addition toimiquimod and fatty acid. An ointment of the invention contains aneffective amount of imiquimod, such as between about greater than 1percent and about 4.25 percent by weight of imiquimod; about 3 percentto about 45 percent, more preferably about 3 percent to about 30 percentby weight fatty acid; and about 40 percent to about 95 percent by weightointment base, all weights being based on the total weight of theointment. Optionally, an ointment of the invention can also containemulsifiers, emollients and thickeners.

A pressure-sensitive adhesive composition of the invention containsimiquimod, fatty acid, and an adhesive. The adhesives utilized in apressure sensitive adhesive composition of the invention are preferablysubstantially chemically inert to imiquimod. A pressure sensitiveadhesive composition of the invention preferably contains an effectiveamount of imiquimod, such as between about greater than 1 percent andabout 4.25 percent by weight of imiquimod; about 10 percent to about 40percent by weight, more preferably of about 15 percent to about 30percent by weight, and most preferably about 20 percent to about 30percent by weight of fatty acid; all weights being based on the totalweight of the pressure sensitive adhesive composition.

Optionally, pressure sensitive adhesive compositions of the inventioncan also contain one or more skin penetration enhancers. The totalamount of skin penetration enhancer(s) present in a pressure sensitiveadhesive composition of the invention is preferably about 3 percent toabout 25 percent by weight, and more preferably about 3 percent to about10 percent by weight based on the total weight of the pressure sensitiveadhesive composition.

A pressure-sensitive adhesive coated sheet material of the invention canbe made from a pressure-sensitive adhesive composition of the inventionin the form of an article such as a tape, a patch, a sheet, or adressing.

A lower dosage strength formulation of the present invention may be usedto topically and/or transdermally administer an effective amount ofimiquimod to effectively treat EGWs with short durations of therapy andwith an acceptable safety profile. Thus, lower dosage strengthformulations according to the present invention can be applied to anysuitable location, for example, topically to dermal, lip and/or mucosalsurfaces. In the case of dermal application, for example, depending onthe concentration, formulation composition, and dermal surface, thetherapeutic effect of imiquimod may extend only to the superficiallayers of the dermal surface or to tissues below the dermal surface.

It should be understood that while lower dosage strength formulations ofthe present invention containing, by weight based on the total weight ofthe formulation, between about 1% and about 4.25% imiquimod arecontemplated, preferably between about 1.5%, 1.75%, 2.0%, 2.25%, 2.5%,2.75%, 3.0%, 3.25%, 3.5%, 3.75%, 4.0% and 4.25% (between about 1.5% andabout 4.25%), and even more preferably between about 2.0%, 2.25%, 2.5%,2.75%, 3.0%, 3.25%, 3.5%, 3.75% and 4.0% (between about 2.0% and about4.0%), and still even more preferably between about 2.5%, 2.75%, 3.0%,3.25%, 3.5% and 3.75% (between about 2.5% and about 3.75%) arecontemplated. Lower dosage strength formulations of the presentinvention that contain about 2.5% imiquimod or about 3.75% imiquimod byweight based on the total weight of the formulation are most preferred.It should also be understood that lower dosage strength imiquimodformulations of the present invention, which have dose proportionaterelease rates as to both the release rates of the imiquimod and thetotal amount of imiquimod released, relative to the Aldara® 5% imiquimodcream, are also preferred.

Thus, it should be understood by those versed in this art that an amountof imiquimod present in a formulation of the present invention will bean effective amount when a formulation of the present invention isapplied daily in accordance with a short duration of therapy asdescribed herein to a targeted area diagnosed with EGWs and permittedfollowing each individual application to remain in contact with thetargeted area for a sufficient time to allow an effective amount ofimiquimod to clear such a disease or warts of the disease, to partiallyclear the number of warts of such a disease, to reduce the number ofwarts, to prevent the recurrence of such a disease without inducingtreatment limiting local skin reactions or adverse events, includingunscheduled rest periods caused by such treatment limiting local skinreactions or adverse events, in an appreciable number of peopleundergoing treatment. For example, when treating EGWs in accordance withthe present invention, an effective amount will achieve a partialclearance in warts as a targeted endpoint, e.g., at least about 40% andpreferably at least about 50% and more preferably at least about 60% andstill more preferably at least about 70% and most preferably at leastabout a 75% reduction in the number of warts in the treatment areacompared with baseline, or at least about 60% and preferably at leastabout 70% and even more preferably at least about 80% and mostpreferably at least about 90% median reduction in the number of warts inthe treatment area compared with baseline as a secondary endpoint, or atleast about 25% complete clearance and preferably at least about 30%complete clearance and even more preferably at least about 35% completeclearance and most preferably at least about 45% complete clearance ofthe warts as a primary endpoint. See, e.g., FIGS. 15-36. By “completeclearance”, as used herein, the term means the absence of clinicallyvisible warts in the treatment area.

Results from use of the lower dosage strength imiquimod formulations inaccordance with the short durations of therapy of the present inventiondemonstrate that lower dosage strength imiquimod formulations dosed oncedaily until complete wart clearance or for up to an eight week treatmentperiod is effective and well-tolerated treatments for EGWs. Thecondensed dosing regimens of the present invention allows for shorttreatment periods, minimizing exposure to imiquimod and furthersupporting an improved benefit-risk profile, as compared withEDA-approved Aldara® 5% imiquimod cream 16 week, thrice-weekly therapy.

Benefits of treatment with the lower dosage strength imiquimodformulations in accordance with the short durations of therapy of thepresent invention include complete clearance or partial clearance (≥30%,preferably ≥40%, preferably ≥50%, preferably ≥60%, even more preferably≥70% even more preferably ≥80% and even more preferably ≥95%) of EGWsfor a majority of the subjects that are treated. See Example 24.

While the present invention has identified what it believes to bepreferred concentrations of imiquimod formulations, numbers ofapplications per week and durations of therapy, it should be understoodby those versed in this art that any effective concentration ofimiquimod in a formulation that delivers an effective amount ofimiquimod and any numbers of application per week during a shortduration of therapy, as described herein, that can effectively treatEGWs, without causing treatment limiting local skin reactions or relatedadverse events, including too many rest periods, is contemplated by thepresent invention.

The above summary of the present invention is not intended to describeeach disclosed embodiment or every implementation of the presentinvention. The description that follows more particularly exemplifiesillustrative embodiments. In several places throughout the application,guidance is provided through lists of examples, which examples can beused in various combinations. In each instance, the recited list servesonly as a representative group and should not be interpreted as anexclusive list.

BRIEF DESCRIPTION OF THE DRAWINGS

The foregoing and other objects, advantages and features of the presentinvention, and the manner in which the same are accomplished, willbecome more readily apparent upon consideration of the followingdetailed description of the invention taken in conjunction with theaccompanying figure and examples, which illustrate an embodiment,wherein:

FIG. 1 shows a schematic representation of a Franz cell;

FIG. 2 shows a summary of microscope pictures of eight 2.5% w/wimiquimod formulations, i.e., formulations 113, 246, 247, 248, 249, 251,252 and 253 (the formulations continued into the stability program areincluded for the 1 kg batches in TABLE 18 and FIG. 9);

FIG. 3 shows a comparison of the mean cumulative amount of imiquimodreleased (μg/cm2) after about 3 h for the membrane release studies (forall the formulations selected for Full thickness skin permeation andstability studies) (mean±sd, where n=4);

FIG. 4 shows a comparison of the average total cumulative reportreleased (μg/cm2) after 3 h for each concentration of imiquimod in theformulations that are tested (mean±sd, where n=4 for 1%, n=16 for 2.5%,n=20 for 3.75% and n=12 for 5%);

FIG. 5 shows a total amount of imiquimod that is recovered followingmass balance for each formulation (See also Tables 35-40 for statisticalanalysts) (mean±sd, refer to Table 34 for n numbers of each sample);

FIG. 6 shows a total amount of imiquimod recovered for each formulationin the receiver fluid, epidermis and dermis combined (mean±sd, refer toTable 34 for n numbers of each sample);

FIG. 7 shows a total amount of imiquimod recovered for the averages ofeach imiquimod concentration from each of the skin matrices.

FIGS. 8A-C show microscopic depiction of 13 imiquimod formulations,i.e., 3M Aldara® imiquimod cream 1 kg batch, Graceway 3M Aldara®imiquimod cream 1 kg batch and formulations 110, 123, 125, 126, 182,183, 195, 197, 250, 256 and 257 (t=0, I., 2, 3 and 6 months)−×400magnification;

FIG. 9 shows microscopic depiction of placebo formulations Pbo1-Pbo4(t=0, 1, 2, 3 and 6 months)−×400 magnification;

FIGS. 10A-B show microscopic depiction of 10 imiquimod formulations,i.e., formulations, 116, 117, 254, 120, 235, 188, 189, 184, 255, 124,after 1 month stability (t=0 and 1 month)−×400 magnification;

FIG. 11 shows a comparison of the mean amount of imiquimod that isreleased (μg/cm2) over a 3 hour period for the 3M Aldara® imiquimodcream 1 kg batch, the 3M Aldara® imiquimod cream sachet, the Graceway 3MAldara® imiquimod cream 1 kg batch and formulation 257, a 1% imiquimodformulation (mean±sd, where n=4);

FIG. 12 shows a comparison of the mean amount of imiquimod that isreleased (μg/cm2) over a 3 hour period for four 2.5% imiquimodformulations, i.e., formulations 110, 123, 125 and 250 (mean±sd, wheren=4).

FIG. 13 shows a comparison of the mean amount of imiquimod that isreleased (ug/cm2) over a 3 hour period for five 3.75% imiquimodformulations, i.e., formulations 182, 183, 195, 197 and 256 (mean±sd,where n=4); and

FIG. 14 shows a comparison of the mean amount of imiquimod released(μg/cm²) over a 3 hour period for the 2.5% (▴), 3.75% (·), 3M Aldara®imiquimod cream batch (▪), Graceway Aldara® imiquimod cream 1 kg batch(▪) and formulation 257 imiquimod formulations (▪) (mean±sd, where n=4).

FIG. 15 shows complete clearance rates observed in the intent-to-treat(111) population at the end of one study of a lower-dose imiquimodtreatment of genital warts. Subjects received treatment for 8 weeks oruntil complete clearance, whichever occurred sooner. Bars Marked with **show statistically significant difference from placebo. The verticallines represent 95% confidence intervals.

FIG. 16 shows complete clearance rates observed in the Per Protocol (PP)population at the end of one study of a lower-dose imiquimod treatmentof genital warts. Bars Marked with ** show statistically significantdifference from placebo. The thick vertical lines represent 95%confidence intervals.

FIG. 17 shows complete clearance rates vs analysis week during theevaluation period observed in the intent-to-treat (ITT) population inone study of a lower-dose imiquimod treatment of genital warts.

FIG. 18 shows complete clearance rates vs analysis week during theevaluation period observed in the Per Protocol (PP) population in onestudy of a lower-dose imiquimod treatment of genital warts.

FIG. 19 shows partial (≥75%) clearance rates observed in theintent-to-treat (ITT) population at the end of one study of a lower-doseimiquimod treatment of genital warts. Partial clearance was defined asat least a 75% reduction in the number of EGW lesions compared tobaseline at anytime point during the study. Bars marked with the ** showstatistically significant difference from placebo. Bars marked with ##show statistically significant difference from 2.5%. The vertical linesrepresent 95% confidence intervals.

FIG. 20 shows partial (≥75%) clearance rates observed in the PerProtocol (PP) population at the end of one study of a lower-doseimiquimod treatment of genital warts.

FIG. 21 shows ≥50% clearance rates observed in the intent-to-treat (ITT)population at the end of one study of a lower-dose imiquimod treatmentof genital warts. Bars marked with the ** show statistically significantdifference from placebo. Bars marked with show statistically significantdifference from 2.5%. The thick vertical lines represent 95% confidenceintervals.

FIG. 22 shows ≥50% clearance rates vs analysis week during theevaluation period observed in the intent-to-treat (ITT) population inone study of a lower-dose imiquimod treatment of genital warts. 50%clearance is defined as at least a 50% reduction in the number of wartsin the treatment area compared with Baseline. Points marked with ** showstatistically significant difference from placebo. Subjects receivedtreatment for 8 weeks or until complete clearance, whichever was sooner.

FIG. 23 shows mean percent change from baseline in wart count vs.analysis week observed in the intent-to-treat (ITT) population in onestudy of a lower-dose imiquimod treatment of genital warts.PCFBL=Percent Change from Baseline. Points marked with the ** showstatistically significant difference from placebo. Subjects receivedtreatment for 8 weeks or until complete clearance, whichever was sooner.

FIG. 24 shows mean local skin reaction sum score by analysis week,safety population, in one study of a lower-dose imiquimod treatment ofgenital warts.

FIG. 25 shows complete clearance rates observed in the intent-to-treat(ITT) population at the end of one study of a lower-dose imiquimodtreatment of genital warts.

FIG. 26 shows complete clearance rates observed in the Per Protocol (PP)population at the end of one study of a lower-dose imiquimod treatmentof genital warts.

FIG. 27 shows complete clearance rates vs analysis week during theevaluation period observed in the intent-to-treat (ITT) population inone study of a lower-dose imiquimod treatment of genital warts, Pointsmarked with the ** show statistically significant difference fromplacebo. Points marked with the ## show statistically significantdifference from 2.5%. Subjects received treatment for 8 weeks or untilcomplete clearance, whichever was sooner.

FIG. 28 shows complete clearance rates vs analysis week during theevaluation period observed in the Per Protocol (PP) population in onestudy of a lower-dose imiquimod treatment of genital warts. Pointsmarked with the ** show statistically significant difference fromplacebo. Points marked with the ## show statistically significantdifference from 2.5%. Subjects received treatment for 8 weeks or untilcomplete clearance, whichever was sooner.

FIG. 29 shows partial (≥75%) clearance rates observed in theintent-to-treat (ITT) population at the end of one study of a lower-doseimiquimod treatment of genital warts. Partial clearance was defined asat least a 75% reduction in the number of EGW lesions compared tobaseline at anytime point during the study. Bars marked with the ** showstatistically significant difference from placebo. Bars marked with ##show statistically significant difference from 2.5%. The thick verticallines represent 95% confidence intervals.

FIG. 30 shows partial (≥75%) clearance rates observed in the PerProtocol (PP) population at the end of one study of a lower-doseimiquimod treatment of genital warts. Bars marked with the ** showstatistically significant difference from placebo. Bars marked with ##show statistically significant difference from 2.5%. The thick verticallines represent 95% confidence intervals.

FIG. 31 shows ≥50% clearance rates observed in the intent-to-treat (ITT)population at the end of one study of a lower-dose imiquimod treatmentof genital warts. Bars marked with the statistically significantdifference from placebo. Bars marked with ## show statisticallysignificant difference from 2.5%. The thick vertical lines represent 95%confidence intervals.

FIG. 32 shows ≥50% clearance rates vs analysis week during theevaluation period observed in the intent-to-treat (ITT) population inone study of a lower-dose imiquimod treatment of genital warts. 50%clearance was defined as at least a 50% reduction in the number of wartsin the treatment area compared with Baseline. Points marked with ** showstatistically significant difference from placebo. Points marked with ##show statistically significant difference from 2.5%. Subjects receivedtreatment for 8 weeks or until complete clearance, whichever was sooner.

FIG. 33 shows mean percent change from baseline in wart count vs.analysis week observed in the intent-to-treat (ITT) population in onestudy of a lower-dose imiquimod treatment of genital warts.PCFBL=Percent Change from Baseline. Points marked with the ** showstatistically significant difference from placebo. Points marked with ##show statistically significant difference from 2.5%, Subjects receivedtreatment for 8 weeks or until complete clearance, whichever was sooner.

FIG. 34 shows mean local skin reaction sum score by analysis week,safety population, in one study of a lower-dose imiquimod treatment ofgenital warts.

FIG. 35 shows mean serum concentrations of imiquimod and imiquimodmetabolites on Day 1 (linear and semi-log scale).

FIG. 36 shows mean serum concentrations of imiquimod and imiquimodmetabolites on Day 21 (linear and semi-log scale).

DETAILED DESCRIPTION OF THE INVENTION

By way of illustrating and providing a more complete appreciation of thepresent invention and many of the attendant advantages thereof, thefollowing detailed description and examples are given concerning thenovel methods and compositions.

In one aspect, the present invention relates to a pharmaceuticalcomposition comprising imiquimod and a pharmaceutically acceptablevehicle for imiquimod, which vehicle comprises a fatty acid. While thepresent invention may be embodied in many different focus, severalspecific embodiments are discussed herein with the understanding thatthe present disclosure is to be considered only as an exemplification ofthe principles of the invention, and it is not intended to limit theinvention to the embodiments described or illustrated.

As used in the specification and claims, the phrase “substantiallyless-irritating” designates formulations that do not cause unacceptableskin irritation in conventional repeat skin irritation tests in albinorabbits such as that described in Draize et al., “Appraisal of theSafety of Chemicals in Food, Drugs and Cosmetics”, prepared by theDivision of Pharmacology of the Food and Drug Administration, publishedoriginally in 1959 by the Association of Food and Drug Officials of theUnited States; Topeka, Kans. (2nd priming 1965), incorporated herein byreference.

Unless otherwise indicated, all numbers expressing quantities, ratios,and numerical properties of ingredients, reaction conditions, and soforth used in the specification and claims are to be understood as beingmodified in all instances by the term “about”.

All parts, percentages, ratios, etc. herein are by weight unlessindicated otherwise. As used herein, the singular forms “a” or “an”“the” are used interchangeably and intended to include the plural formsas well and fall within each meaning, unless expressly stated otherwise.Also as used herein, “at least one” is intended to mean “one or more” ofthe listed element. Singular word forms are intended to include pluralword forms and are likewise used herein interchangeably whereappropriate and fall within each meaning, unless expressly statedotherwise. Except where noted otherwise, capitalized and non-capitalizedforms of all terms fall within each meaning.

By the term “bioequivalence or bioequivalent”, as used herein, it refersto lower dosage strength formulations in which they are pharmaceuticallyequivalent and their bioavailability (rate and extent of absorption)after administration in the same molar dosage or amount are similar tosuch a degree that their therapeutic effects, as to safety and efficacy,are essentially the same. In other words, bioequivalence orbioequivalent means the absence of a significant difference in the rateand extent to which imiquimod becomes available from such formulationsat the site of imiquimod action when administered at the same molar doseunder similar conditions, e.g., the rate at which imiquimod can leavesuch a formulation and the rate at which imiquimod can either cross thestratum corneum and/or become available at the site of action to treatexternal genital or perineal warts (EGWs). In other words, there is ahigh degree of similarity in the bioavailabilities of two imiquimodpharmaceutical products (of the same galenic form) from the same molardose, that are unlikely to produce clinically relevant differences intherapeutic effects, or adverse reactions, or both. The terms“bioequivalence”, as well as “pharmaceutical equivalence” and“therapeutic equivalence” are also used herein as defined and/or used by(a) the FDA, (b) the Code of Federal Regulations (“C.F.R.”), Title 21,and/or (c) Health Canada.

By the term “bioavailability or bioavailable”, as used herein, it meansgenerally the rate and extent of absorption of imiquimod into thesystemic circulation and, more specifically, the rate or measurementsintended to reflect the rate and extent to which imiquimod becomesavailable at the site of action or is absorbed from a drug product andbecomes available at the site of action. In other words, and by way ofexample, the extent and rate of imiquimod absorption from a lower dosagestrength formulation of the present invention as reflected by atime-concentration curve of imiquimod in systemic circulation.

By “pharmaceutical equivalence or pharmaceutically equivalent”, as usedherein, it refers to lower dosage strength imiquimod formulations of thepresent invention that contain the same amount of imiquimod, in the samedosage forms, but not necessarily containing the same inactiveingredients, for the same route of administration and meeting the sameor comparable compendia or other applicable standards of identity,strength, quality, and purity, including potency and, where applicable,content uniformity and/or stability.

By “therapeutic equivalence or therapeutically equivalent”, it is meantherein to mean those lower dosage strength imiquimod formulations which(a) will produce the same clinical effect and safety profile whenpracticing the short durations of therapy to treat EGWs in accordancewith the present invention and (b) are pharmaceutical equivalents, e.g.,they contain imiquimod in the same dosage form, they have the same routeof administration; and they have the same imiquimod strength. In otherwords, therapeutic equivalence means that a chemical equivalent of animiquimod lower dosage strength imiquimod formulation of the presentinvention (i.e., containing the same amount of imiquimod in the samedosage form) when administered to the same individuals in the samedosage regimen will provide essentially the same efficacy and toxicity.

By “T_(max)”, it is meant herein to mean the time when the maximumimiquimod serum concentration is reached at steady state followingtopical application of a lower dosage strength imiquimod formulation ofthe present invention, i.e., when the rate of imiquimod absorptionequals the rate of imiquimod elimination. In other words, the time thatC_(max) is observed for imiquimod.

By “C_(max)”, it is meant herein to refer to the maximum imiquimod serumconcentration that is reached at steady state following topicalapplication of a lower dosage strength imiquimod formulation of thepresent invention, i.e., when the rate of imiquimod absorption equalsthe rate of imiquimod elimination. In other words, it is the maximumserum concentration; the highest serum concentration observed during theimiquimod dosing or sampling interval.

By “C_(min)”, it is meant herein to refer to the minimum measurableimiquimod serum concentration; e.g., imiquimod serum concentration thatis observed immediately prior to dosing on Days 7, 14, 21 and 22 (24hours post-dose).

By “T_(1/2)”, it is meant herein to mean the time required for half ofthe quantity of maximum imiquimod serum concentration to be eliminatedonce steady state is achieved following topical application of a lowerdosage strength imiquimod formulation of the present invention. Forexample, the apparent elimination half-life for imiquimod, that iscalculated as about 0.693/λ_(z), in accordance with Example 24.

By “AUC₀₋₂₄”, it is meant herein to mean the area under the serumimiquimod concentration versus a 24 hour time curve following topicalapplication of a lower dosage strength imiquimod formulation of thepresent invention, i.e., a measure of imiquimod exposure over a 24 hourperiod. For example, the area under the imiquimod serum concentrationversus time curve, from 0 to 24 hours, that is calculated using thelinear trapezoid rule or extrapolated to 24 hours in cases wherereportable values are not obtainable up to that time point.

By “AUC_(0-t)”, it is meant herein to mean the area under the imiquimodserum concentration versus time curve, from 0 to the time of the lastnon-zero concentration on Day 1; that is calculated using the lineartrapezoid rule.

By “R_(AUC)”, it is meant herein to mean the accumulation ratio; thatare calculated as the AUC₀₋₂₄ value during multiple-imiquimod doseadministration divided by the AUC₀₋₂₄ value following the first dose(i.e., Day 21/Day 1); or the accumulation ratios that are calculated foran imiquimod metabolite only if sufficient non-zero time points areavailable to reasonably estimate AUC₀₋₂₄.

By “AUC_(0-inf)”, it is meant herein to mean the area under theimiquimod serum concentration versus time curve, from 0 to infinity;AUC_(0-inf) that is calculated on Day 1 asAUC_((0-inf))=AUC_((o-t))+Ct/K_(et) (where C_(t)=the fitted lastnon-zero concentration, AUC_(0-t)=the AUC from time zero to the time ofthe last non-zero concentration and K_(et)=the elimination rateconstant).

By “R_(Cmax).”, it is meant herein to mean the accumulation ratio;calculated as the C_(max). value during multiple-dose administrationdivided by the C_(max) value following the first dose (i.e., Day 21/Day1).

By “λz_(EFF)”, it is meant herein to mean the effective elimination rateconstant, calculated as −ln(1−1/R_(Auc))/tau.

By “T_(1/2 EFF)”, it is meant herein to mean the effective half-life foraccumulation; calculated as 0.693/λz_(EFF).

By “λz”, it is meant to refer to an elimination rate constant, i.e., therate at which imiquimod disappears from the site of measurement oncesteady state is achieved following topical application of a lower dosagestrength imiquimod formulation of the present invention. In other words,the apparent elimination rate constant; that is calculated using linearregression on the terminal portion of the In concentration versus timeprofile.

By “geometric mean”, it refers a statistical average of a set oftransformed numbers often used to represent a central tendency in highlyvariable data. It is calculated from data transformed using powers orlogarithms and then transformed back to original scale after averaging.

By “geometric mean ratio”, it refers to a ratio of two geometric means,where the “geometric LS mean test” is the numerator of the geometricmean ratio, and the “geometric LS mean reference” is the denominator ofthe geometric mean ratio.

By “RH”, it refers herein to relative humidity.

By “cPs, it refers herein to centipoise.

By “h”, it refers herein to hours.

By “ITT”, it refers to an intent-to-treat population.

By “Pbo, it refers to placebo.

By “EOS”, it refers to End of Study.

By “V”, it refers to vehicle.

By “AE”, it refers herein to adverse events.

The present invention provides pharmaceutical formulations such ascreams, ointments, foams, gels, lotions and adhesive coatings thatcontain imiquimod and a fatty acid such as isostearic, linoleic,unrefined oleic acid, refined oleic acid, such as Super Refined® oleicacid NF (e.g., a highly purified oleic acid, i.e., an oleic acid whichhas low polar impurities, such as peroxides, a low peroxide value and ismarketed by CRODA; see e.g., www.crodausa.com) and mixtures thereof. Theformulations of the invention provide desirable skin penetrability ofthe imiquimod.

The compound imiquimod is a known antiviral agent that is also known toinduce interferon biosynthesis. It can be prepared using the methoddisclosed in U.S. Pat. No. 4,689,338, the disclosure of which isincorporated herein by reference in its entirety. The compound can beused to treat external genital and perineal wart (EGWs). The amount ofimiquimod present in a formulation of the present invention will be aneffective amount to treat EGWs to achieve total wart clearance orpartial wart reduction or clearance, to prevent the recurrence of such adisease and/or to promote immunity against such a disease with anacceptable safety profile. An example of an effective amount ofimiquimod in a formulation of the present invention is between about 1.0percent and about 4.25 percent by weight based on the total weight of aformulation, more preferably between about 1.5%, 1.75%, 2.0%, 2.25%,2.5%, 2.75%, 3.0%, 3.25%, 3.5%, 3.75%, 4.0% and 4.25% (between about1.5% and about 4.25%), even more preferably between about 2.0%, 2.25%,2.5%, 2.75%, 3.0%, 3.25%, 3.5%, 3.75% and 4.0% (between about 2.0% andabout 4.0%), and still even more preferably between about 2.5%, 2.75%,3.0%, 3.25%, 3.5% and 3.75% (between about 2.5% and about 3.75%).Imiquimod formulations of the present invention that contain about 2.5%imiquimod or about 3.75% imiquimod by weight based on the total weightof the formulation are most preferred.

Likewise, a shortened period or duration, as contemplated by the presentinvention, will be for reduced periods of time effective to treat EGWsas discussed herein above, e.g., up to eight weeks or less, againdepending upon the lower dosage strength imiquimod formulation of thepresent invention that is selected for daily application, or up to sixweeks or less or up to four weeks or less. By way of example, shortperiods of treatment with lower dosage strength imiquimod formulationsfor treating EGWs, include:

applying an effective amount of imiquimod, such as via the lower dosagestrength imiquimod formulations of the present invention to the areaaffected with EGWs, as follows: applying an effective amount once perday to the wart treatment area until complete clearance is achieved, forexample, between about 28 doses and 56 doses applied once per day, suchas applying an effective amount once per day up to about eight weeks orless, up to about six weeks or less, or up to about four weeks or lessto thereby treat EGWs.

A fatty acid such as isostearic acid, palmitic acid, stearic acid,linoleic acid, refined oleic acid, such as Super Refined® oleic acid NF(e.g., a highly purified oleic acid, i.e., an oleic acid which has lowpolar impurities, such as peroxides, a low peroxide value and ismarketed by CRODA; see e.g., www.crodausa.com), an unrefined oleic acidblended with effective amounts of antioxidants or mixtures thereof areincorporated into formulations of the present invention. The totalamount of fatty acid present in a formulation is preferably betweenabout 3 percent and about 45 percent by weight based on the total weightof a formulation. It should be understood that when oleic acid isselected as a fatty acid, that stability may present issue. Thus,stabilizers, such as anti-oxidants and the like, may be required topreserve pharmaceutical elegance and stability over the life of theoleic acid formulation.

A pharmaceutical formulation of the invention can be in a form such as acream, an ointment, a foam, a gel, a lotion, a pressure-sensitiveadhesive composition, or other forms known to those skilled in the art,each particular form containing imiquimod and fatty acid in particularamounts, and optionally containing various additional elements. Thepreferred amounts of drug and fatty acid, and the amounts and types ofoptional elements used in formulations of the invention are discussedbelow with particular reference to creams, ointments and adhesivecompositions.

A cream according to the invention contains1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine and fatty acid.

The amount of 1-isobutyl-1H-imidazo[4,5-c]-quinolin-4-amine present in acream is preferably about 0.5 percent to about 9 percent by weight, andmore preferably about 1 percent to about 5 percent by weight, and morepreferably about 2.5% to about 3.75%, based on the total weight of thecream.

The total amount of fatty acid present in a cream of the invention ispreferably about 3 percent to about 45 percent by weight, and morepreferably about 5 percent to about 25 percent by weight, based on thetotal weight of the cream.

Optionally, a cream of the present invention can contain emollients,emulsifiers, thickeners, and/or preservatives.

Emollients such as long chain alcohols, e.g., cetyl alcohol, stearylalcohol and cetearyl alcohol; hydrocarbons such as petrolatum and lightmineral oil; or acetylated lanolin can be included in a cream of theinvention. A cream can contain one or more of these emollients. Thetotal amount of emollient in a cream of the invention is preferablyabout 5 percent to about 30 percent, and more preferably about 5 percentto about 10 percent by weight based on the total weight of the cream.

Emulsifiers such as nonionic surface active agents, e.g., polysorbate 60(available from ICI Americas), sorbitan monostearate, polyglyceryl-4oleate, and polyoxyethylene(4)lauryl ether or trivalent cationic a creamof the invention. A cream can contain one or more emulsifiers. Generallythe total amount of emulsifier is preferably about 2 percent to about 14percent, and more preferably about 2 percent to about 6 percent byweight based on the total weight of the cream.

Pharmaceutically acceptable thickeners, such as Xanthum gum, Guar gum,Veegum Gum™ K (available from R. T. Vanderbilt Company, Inc.), and longchain alcohols (i.e. cetyl alcohol, stearyl alcohol or cetearyl alcohol)can be used. A cream can contain one or more thickeners. The totalamount of thickener present is preferably about 3 percent to about 12percent by weight based on the total weight of the cream.

Preservatives such as methylparaben, propylparaben and benzyl alcoholcan be present in a cream of the invention. The appropriate amount ofsuch preservative(s) is known to those skilled in the art.

Optionally, an additional solubilizing agent such as benzyl alcohol,lactic acid, acetic acid, stearic acid, salicylic acid, anyalpha-hydroxy acid such as glycolic acid, or hydrochloric acid can beincluded in a cream of the invention.

If an additional solubilizing agent is used, the amount present ispreferably about 1 percent to about 12 percent by weight based on thetotal weight of the cream.

Optionally, a cream of the invention can contain a humectant such asglycerin, skin penetration enhancers such as butyl stearate, andadditional solubilizing agents.

Generally, a cream consists of an oil phase and a water phase mixedtogether to form an emulsion. Preferably, the amount of water present ina cream of the invention is about 45 percent to about 85 percent byweight based on the total weight of the cream. The oil phase of a creamof the invention can be prepared by first combining the1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine or1-(2-methylpropyl)-1H-imidazo [4,5-c]quinolin-4-amine and the fatty acid(if the cream contains benzyl alcohol it can also be added at thispoint) and heating with occasional stirring to a temperature of about50° C. to 85° C. When the 1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amineor 1-(2-methylpropyl)-1H-imidazo [4,5-c]quinolin-4-amine appears to becompletely dissolved, the remaining oil phase ingredients are added andheating is continued until dissolution appears to be complete.

The water phase can be prepared by combining all other ingredients andheating with stirring until dissolution appears to be complete.

The creams of the invention are generally prepared by adding the waterphase to the oil phase with both phases at a temperature of about 65° C.to 75° C. The resulting emulsion is mixed with a suitable mixerapparatus to give the desired cream.

An ointment of the invention contains an ointment base in addition to1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine and fatty acid.

The amount of 1-isobutyl-1H-imidazo[4,5-c]-quinolin-4-amine present inan ointment of the invention is preferably about 0.5 percent to about 9percent, and more preferably about 0.5 percent to about 5 percent byweight based on the total weight of the ointment.

The total amount of fatty acid present in an ointment of the inventionis preferably about 3 percent to about 45 percent, and more preferablyabout 3 percent to about 25 percent based on the total weight of theointment.

A pharmaceutically acceptable ointment base such as petrolatum orpolyethylene glycol 400 (available from Union Carbide) in combinationwith polyethylene glycol 3350 (available from Union Carbide) can beused. The amount of ointment base present in an ointment of theinvention is preferably about 60 percent to about 95 percent by weightbased on the total weight of ointment.

Optionally, an ointment of the invention can also contain emollients,emulsifiers and thickeners. The emollients, emulsifiers, and thickenersand the preferred amounts thereof described above in connection withcreams are also generally suitable for use in an ointment of theinvention.

An ointment according to the invention can be prepared by combining1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine with fatty acid and heatingwith occasional stirring to a temperature of about 65° C. When the1-isobutyl-1H-imidazo[4,5-c]-quinolin-4-amine or1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine appears to becompletely dissolved, the remaining ingredients are added and heated toabout 65.° C. The resulting mixture is mixed with a suitable mixer whilebeing allowed to cool to room temperature.

A pressure-sensitive adhesive composition of the invention contains1-isobutyl-1H-imidazo [4,5-c]-quinolin-4-amine or1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine, fatty acid, and apressure sensitive adhesive polymer.

The amount of 1-isobutyl-1H-imidazo[4,5-c]-quinolin-4-amine or1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine present in apressure sensitive adhesive composition of the invention is preferablyabout 0.5 percent to about 9 percent by weight, and more preferablyabout 3 percent to about 7 percent by weight based on the total weightof the adhesive composition. The amount of fatty acid present ispreferably about 10 percent to about 40 percent by weight, morepreferably about 15 percent to about 30 percent by weight, and mostpreferably about 20 percent to about 30 percent by weight, based on thetotal weight of the adhesive composition.

Preferably, the adhesive polymer utilized in a pressure sensitiveadhesive composition of the invention is substantially chemically inertto 1-isobutyl-1H-imidazo[4,5-c]-quinolin-4-amine or1-(2-methylpropyl)-1H-imidazo [4,5-c] quinolin-4-amine. The adhesivepolymer is preferably present in an amount of about 55 percent to about85 percent by weight based on the total weight of the composition.Suitable adhesive polymers include acrylic adhesives that contain, as amajor constituent (i.e., at least about 80 percent by weight of allmonomers in the polymer), a hydrophobic monomeric acrylic or methacrylicacid ester of an alkyl alcohol, the alkyl alcohol containing 4 to 10carbon atoms. Examples of suitable monomers are those discussed below inconnection with the “A Monomer”. These adhesive polymers can furthercontain minor amounts of other monomers such as the “B Monomers” listedbelow.

Preferred adhesives include acrylic pressure-sensitive adhesivecopolymers containing A and B Monomers as follows: Monomer A is ahydrophobic monomeric acrylic or methacrylic acid ester of an alkylalcohol, the alkyl alcohol containing 4 to 10 carbon atoms, preferably 6to 10 carbon atoms, more preferably 6 to 8 carbon atoms, and mostpreferably 8 carbon atoms. Examples of suitable A Monomers are n-butyl,n-pentyl, n-hexyl, isoheptyl, n-nonyl, n-decyl, isohexyl, 2-ethyloctyl,isooctyl and 2-ethylhexyl acrylates. The most preferred A Monomer isisooctyl acrylate.

Monomer B is a reinforcing monomer selected from the group consisting ofacrylic acid; methacrylic acid; alkyl acrylates and methacrylatescontaining 1 to 3 carbon atoms in the alkyl group; acrylamide;methacrylamide; lower alkyl-substituted acrylamides (i.e., the alkylgroup containing 1 to 4 carbon atoms) such as tertiary-butyl acrylamide;diacetone acrylamide; n-vinyl-2-pyrrolidone; vinyl ethers such as vinyltertiary-butyl ether; substituted ethylenes such as derivatives ofmaleic anhydride, dimethyl itaconate and monoethyl formate and vinylperfluoro-n-butyrate. The preferred B Monomers are acrylic acid,methacrylic acid, the above-described alkyl acrylates and methacrylates,acrylamide, methacrylamide, and the above-described lower alkylsubstituted acrylamides. The most preferred B Monomer is acrylamide.

In one embodiment of a pressure-sensitive adhesive composition of theinvention, the pressure-sensitive adhesive copolymer containing A and BMonomers as set forth above preferably contains the A Monomer in anamount by weight of about 80 percent to about 98 percent of the totalweight of all monomers in the copolymer. The A Monomer is morepreferably present in an amount by weight of about 88 percent to about98 percent, and is most preferably present in an amount by weight ofabout 91 percent to about 98 percent. The B Monomer in such a copolymeris preferably present in the pressure-sensitive adhesive copolymer in anamount by weight of about 2 percent to about 20 percent, more preferablyabout 2 percent to about 12 percent, and most preferably 2 to 9 percentof the total weight of the monomers in the copolymer.

In another embodiment of a pressure-sensitive adhesive composition ofthe invention, the adhesive copolymer comprises about 60 to about 80percent by weight (and preferably about 70 to about 80 percent byweight) of the above-mentioned hydrophobic monomeric acrylic ormethacrylic acid ester of an alkyl alcohol (i.e., Monomer A describedabove) based on the total weight of all monomers in the copolymer; about4 to about 9 percent by weight based on the total weight of all monomersin the copolymer of a reinforcing monomer selected from the groupconsisting of acrylic acid, methacrylic acid, an alkyl acrylate ormethacrylate containing 1 to 3 carbon atoms in the alkyl group,acrylamide, methacrylamide, a lower alkyl-substituted acrylamide,diacetone acrylamide and N-vinyl-2-pyrrolidone; and about 15 to about 35percent by weight (and preferably about 15 to about 25 percent byweight) of vinyl acetate based on the total weight of all monomers inthe copolymer. In this embodiment the preferred acrylic or methacrylicacid ester is isooctyl acrylate and the preferred reinforcing monomer isacrylamide.

The above described adhesive copolymers are known, and methods ofpreparation therefore are well known to those skilled in the art, havingbeen described for example, in U.S. Pat. No. 24,906 (Ulrich), thedisclosure of which is incorporated herein by reference. Thepolymerization reaction can be carried out using a free radicalinitiator such as an organic peroxide (e.g., benzoylperoxide) or anorganic azo compound (e.g., 2,2′-azobis(2,4-dimethylpentanenitrile),available under the trade designation “Vazo 52” from DuPont).

Since pressure-sensitive adhesives such as those described above areinherently rubbery and tacky and are suitably heat and light stable,there is no need to add tackifiers or stabilizers. However, such can beadded if desired.

Optionally, a pressure sensitive adhesive composition of the inventioncan also contain one or more skin penetration enhancers such as glycerylmonolaurate, ethyl oleate, isopropyl myristate, diisopropyl adipate andN,N-dimethyldodecylamine-N-oxide, either as a single ingredient or as acombination of two or more ingredients. The skin penetration enhancer(s)preferably form a substantially homogeneous mixture with the pressuresensitive adhesive polymer or copolymer. The total amount of skinpenetration enhancer(s) present in a pressure sensitive adhesivecomposition of the invention is preferably about 3 percent to about 25percent by weight, more preferably about 3 percent to about 10 percentby weight based on the total weight of the adhesive composition.

When the skin penetration enhancer is a single ingredient, it ispreferably a skin penetration enhancer such as isopropyl myristate,diisopropyl adipate, ethyl oleate, or glyceryl monolaurate.

When a combination skin penetration enhancer is used, it is preferably acombination such as: ethyl oleate with glyceryl monolaurate; ethyloleate with N,N-dimethyldodecylamine-N-oxide; glyceryl monolaurate withN,N-dimethyldodecylamine-N-oxide; and ethyl oleate with both glycerylmonolaurate and N,N-dimethyldodecylamine-N-oxide.

A pressure-sensitive adhesive composition of the invention can beprepared by combining dry adhesive,1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine, fatty acid, and skinpenetration enhancer(s) with an organic solvent. The preferred organicsolvents are methanol and ethyl acetate. The total solids content of theadhesive coating is preferably in the range of about 15 percent to about40 percent, and more preferably in the range of about 20 to about 35percent based on the total weight of the adhesive coating. The resultingmixture is shaken or mixed for a period of about 20 to 72 hours. Whenthis method is used it is preferred that the1-isobutyl-1H-imidazo[4,5-c]-quinolin-4-amine be in micronized form(i.e., particle size of 1-2 microns in diameter). Optionally, themixture can be heated during shaking.

In a preferred method, the 1-isobutyl-1H-imidazo[4,5-c]-quinolin-4-amineor 1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine is combined withthe fatty acid and shaken at 40° C. until there appears to be completedissolution. The remaining ingredients are added and the mixture isshaken for a period of about 20 to 72 hours.

The pressure-sensitive adhesive compositions described above arepreferably coated onto one surface of a suitable backing of sheetmaterial, such as a film, to form a pressure-sensitive adhesive coatedsheet material. A pressure-sensitive adhesive coated sheet material ofthe invention can be prepared by knife coating a suitable release linerto a predetermined uniform thickness with a wet adhesive formulation.This adhesive coated release liner is then dried and laminated onto abacking using conventional methods. Suitable release liners includeconventional release liners comprising a known sheet material, such as apolyester web, a polyethylene web, or a polystyrene web, orpolyethylene-coated paper, coated with a suitable silicone-type coatingsuch as that available under the trade designation Daubert 164Z, fromDaubert Co. The backing can be occlusive, non-occlusive or a breathablefilm as desired. The backing can be any of the conventional materialsfor pressure-sensitive adhesive tapes, such as polyethylene,particularly low density polyethylene, linear low density polyethylene,high density polyethylene, randomly-oriented nylon fibers,polypropylene, ethylene-vinylacetate copolymer, polyurethane, rayon andthe like. Backings that are layered, such aspolyethylene-aluminum-polyethylene composites are also suitable. Thebacking should be substantially non-reactive with the ingredients of theadhesive coating. The presently preferred backing is low densitypolyethylene.

The pressure-sensitive adhesive coated sheet material of the inventioncan be made in the form of an article such as a tape, a patch, a sheet,a dressing or any other form known to those skilled in the art.

Preferably, an article in the form of a patch is made from an adhesivecoated sheet material of the invention and applied to the skin of amammal. The patch is replaced as necessary with a fresh patch tomaintain the particular desired therapeutic effect of the1-isobutyl-1H-imidazo [4,5-c] quinolin-4-amine.

The inherent viscosity values reported in the examples below wereobtained by the conventional method used by those skilled in the art.The measurement of the viscosity of dilute solutions of the adhesive,when compared to controls run under the same conditions, clearlydemonstrates the relative molecular weights. It is the comparativevalues that are significant; absolute figures are not required. In theexamples, the inherent viscosity values were obtained using aCannon-Fenske #50 viscometer to measure the flow time of 10 ml of apolymer solution (0.2 g polymer/deciliter tetrahydrofuran, in a waterbath controlled at 25° C.). The examples and the controls were run underidentical conditions. The test procedure followed and the apparatus usedare explained in detail in the Textbook of Polymer Science, F. W.Billmeyer, Wiley-Interscience, 2nd Edition, 1971 under: Polymer chainsand their characterization, D. Solution Viscosity and Molecular Size, pp84-85, the disclosure and textbook of which is incorporated byreference.

As indicated herein above, and in accordance with the present invention,the present invention contemplates bioequivalent or interchangeablelower dosage strength imiquimod formulations. By way of an example,bioequivalent or interchangeable 3.75% lower dosage strength imiquimodtopical formulations, as contemplated by the present invention, includethose 3.75% imiquimod formulations that have comparable in-vivo serumprofiles, i.e., wherein the following in-vivo parameters are either thesame or may vary up to about ±25% or more, when such 3.75% formulationsare topically administered daily to the same individuals in the samedosage regimen in accordance with the short durations of therapy of thepresent invention:

By way of example, a 3.75% imiquimod lower dosage strength formulationof the present invention, when approximately 250 mg of such aformulation' (about 9.375 mg imiquimod) or less is applied daily for 21days to EGWs in the genital/perianal area with a total wart area ofgreater than or equal to 100 mm², achieves steady state by about Day 7,and provides an in-vivo serum profile selected from one or more of thefollowing:

(a) a Day 21 mean T_(max) of about 9.7 hours with a standard deviation(“SD”) of about 4.0, a median T_(max) of about 12 hours and a geometricmean T_(max) of about 8.3 hours and a coefficient of variation (“CV”) ofabout 41%;

(b) a Day 21 mean C_(max) of about 0.488 ng/ml with a standard deviationof about 0.368, a median of about 0.45 and a geometric mean C_(max) ofabout 0.39 ng/mL and a coefficient of variation of about 75%;

(c) a Day 21 T_(1/2), of from about 6.8 to about 54 hours and preferablya mean T_(1/2) of about 24.1 hours with a standard deviation of about12, a median T_(1/2) of about 22.8 hours and a geometric mean T_(1/2) ofabout 21 hours and a coefficient of variation of about 51%;

(d) a Day 21 AUC₀₋₂₄ of from about 1.9 to about 14 ng-hr/mL andpreferably a mean AUC₀₋₂₄ of about 6.8 ng·hr/mL with a standarddeviation of about 3.6, a median AUC₀₋₂₄ of about 6.6 ng·hr/mL, and ageometric mean AUC₀₋₂₄ of about 5.8 ng-hr/mL and a coefficient ofvariation of about 53%;

(e) a Day 21 λz of from about 0.013 hr⁻¹ to about 0.102 h⁻¹ andpreferably a mean λz of about 0.037 hr⁻¹ with a standard deviation ofabout 0.02, a median λz of about 0.03 hr⁻¹ and a geometric mean λz ofabout 0.03 hr⁻¹ and a coefficient of variation of about 60%;

(f) a Day 21 C_(min) of from about 0.025 to about 0.47 and preferably amean C_(min) of about 0.158 with an SD of about 0.121, a median C_(min)of about 0.14 and a geometric mean C_(min) of about 0.11 and acoefficient of variation of about 77%;

(g) at Day 14/7 (a ratio of the trough concentration at Day 14 over thetrough concentration at Day 7), a trough concentration geometric meanratio of about 1.13 with a 90% confidence interval (“CI”) within a rangeof between about 0.7 and about 1.7;

(h) at Day 21/14 (a ratio of the trough concentration at Day 21 over thetrough concentration at Day 14), a trough concentration geometric meanratio of about 0.84 with a 90% confidence interval (“CI”) within a rangeof between about 0.5 and about 1.3;

(i) at Day 22/21 (a ratio of the trough concentration at Day 22 over thetrough concentration at Day 21) a trough concentration geometric meanratio of about 1.12 with a 90% confidence interval (“CI”) within a rangeof between about 0.7 and about 1.6;

(j) a mean peak imiquimod serum concentration of about 0.488 ng/mL atDay 21;

(k) a Day 21 RAUC of from about 0.6 to about 7 and preferably a meanRAUC of about 2.2 with a standard deviation of about 1.8, a median RAUCof about 1.8 and a geometric mean RAUC of about 1.7 and a coefficient ofvariation of about 81%;

(l) a Day 21 RC_(max) of from about 0.5 to about 5 and preferably a meanRC_(max) of about 2.3 with a standard deviation of about 1.6, a medianRC_(max) of about 1.7 and a geometric mean RC_(max) of about 1.8 and acoefficient of variation of about 70%;

(m) a Day 21 L λz_(eff) of from about 0.006 h⁻¹ to about 0.09 h⁻¹ andpreferably a mean L λ_(zeff) of about 0.04 with a standard deviation ofabout 0.03, a median L λ_(zeff) of about 0.03 h⁻¹ and a geometric meanLXzeff of about 0.03 hr⁻¹ and a coefficient of variation of about 69%;

(n) a Day 21 T^(1/2) _(eff) of from about 8 hr to about 111 hr andpreferably a mean T^(1/2) _(eff) of about 31 hr with a standarddeviation of about 30, a median T^(1/2) _(eff) of about 22 hr and ageometric mean T^(1/2) _(eff) of about 23 h⁻¹ and a coefficient ofvariation of about 97%;

(o) a Day 21 C_(max) in female patients about 61% higher in femalesubjects than in male subjects (0.676 versus 0.420 ng/mL) and totalsystemic exposure AUC₀₋₂₄ 8% higher in female subjects than in malesubjects (7.192 versus 6.651 ng-hr/mL) when data is not dose normalized;

(p) a Day 21 C_(max) in female patients about 35% higher than in malesubjects (0.583 versus 0.431 ng/mL) and AUC₀₋₂₄ about 6% lower in femalesubjects than in male subjects (6.428 versus 6.858 ng-hr/mL) when usingdose normalization to adjust for differences in dosage and reportedwithout subjects who missed an application of study drug during the lastweek of dosing; and/or

(q) a median T_(max) occurring approximately twice as quickly in femalesubjects (about 6.50 hours) as in male subjects (about 12.0 hours).

In accordance with the present invention, a mean peak serumconcentration is achieved with a 3.75% lower dosage strength imiquimodformulation of Examples 23-26. More specifically, a mean peak serumconcentration of about 0.488 ng/mL is achieved with a 3.75% lower dosagestrength imiquimod formulation of Examples 23-26 after about 9.4 mg ofimiquimod is applied to the affected treatment area each day for up to 8weeks.

Furthermore, this invention provides the following evidence of clinicalefficacy: the wart area decreased by about 45% from a mean of about108.3 mm2 at baseline to about 43.2 mm2 at Day 21, e.g., see Table 145.The P value of <0.0001 for this change from baseline indicated astatistically significant (≤0.050) decrease in wart area after 3 weeksof treatment.

While the lower dosage strength imiquimod pharmaceutical formulations ofthe present invention can be formulated into any form known to the art,such as a cream, an ointment, a foam, a gel, a lotion or apressure-sensitive adhesive composition or patch, it should beunderstood that the creams, ointments, foams, gels and lotions may bepackaged into any suitable container, such as unit-dose sachets orpackets or multi-dose tubes or containers. A packaged amount of animiquimod pharmaceutical formulation contemplated by the presentinvention includes any suitable amount, such as about 250 mg to about500 mg or more, and preferably about 250 mg, about 300 mg, about 350 mg,about 400 mg, about 450 mg or about 500 mg unit-dose sachets or packets.

Examples of various embodiments of the present invention will now befurther illustrated with reference to the following examples. Thus, thefollowing examples are provided to illustrate the invention, but are notintended to be limiting thereof. Parts and percentages are by weightunless otherwise specified. Examples of creams, ointments and pressuresensitive adhesive compositions contemplated by the present inventionare described in U.S. Pat. Nos. 4,689,338 and 5,238,944, which areincorporated herein by reference in their entireties. Percentmodifications for, e.g., imiquimod and vehicle, to generate imiquimodformulations as described herein are likewise contemplated by thepresent invention. In addition, the formulations described and disclosedin U.S. Pat. No. 7,655,672, U.S. Patent Publication No. 2007/0123558,Ser. No. 11/276,324, U.S. Patent Publication No. 2007/0264317, U.S. Ser.No. 11/433,471, U.S. Patent Publication No. 2007/0900550 and PCTPublication No. WO2008098232 (A1), are also contemplated by the presentinvention and are incorporated herein by reference in their entireties.

Preparative Method 1

Laboratory Scale Preparation of Isooctylacrylate/Acrylamide Copolymer

To a 114 gram narrow-mouth glass bottle were added: 18.6 g isooctylacrylate, 1.4 g acrylamide, 0.04 g benzoyl peroxide, 27.0 g ethylacetate and 3.0 g methanol. The solution was purged for thirty fiveseconds with nitrogen at a flow rate of one liter per minute. The bottlewas sealed and placed in a rotating water bath at 55° C. for twenty-fourhours to effect essentially complete polymerization. The polymer wasdiluted with ethyl acetate/methanol (90/10) to 23.2 percent solids andhad a measured inherent viscosity of 1.26 dl/g in ethyl acetate.

Preparative Method 2

Pilot Plant Scale Preparation of Isooctylacrylate/Acrylamide Copolymer

155 kg isooctylacrylate, 11.6 kg acrylamide, 209.1 kg ethyl acetate and23.2 kg methanol were charged to a clean, dry reactor. Medium agitationwas applied. The batch was deoxygenated with nitrogen while heating toan induction temperature of 55° C. 114 g Lucidol™ 70 initiator(available from Pennwalt Corp.) mixed with 2.3 kg ethyl acetate wascharged to the reactor. The temperature was maintained at 55° C.throughout the reaction. After 5.5 hours reaction time, 114 g Lucidol™70 mixed with 2.3 kg ethylacetate were charged to the reactor. After 9.0hours reaction time, an additional 114 g Lucidol™ 70 initiator mixedwith 2.3 kg ethyl acetate were charged to the reactor. The reaction wascontinued until the percent conversion was greater than 98 percent asmeasured by gas chromatographic evaluation of residual monomerconcentration. The resulting polymer solution was diluted to 25-28percent solids with ethyl acetate/methanol (90/10) and had a measuredBrookfield viscosity of 17,000-21,000 centipoises using spindle #4 at 12rpm. The polymer had a measured inherent viscosity of 1.3-1.4 dllg inethyl acetate.

The above-mentioned procedure was found to provide a pressure-sensitiveadhesive that is equivalent in the practice of the present invention toa pressure-sensitive adhesive prepared according to Preparative Method1.

A 25-30 percent solids solution of the isooctyl acrylate:acrylamide(93:7) adhesive copolymer in ethyl acetate/methanol (90:10) was coatedonto a two-sided release liner using a knife-coater and coating at 0.5mm in thickness. The adhesive-coated laminate was dried first at 82° C.for 3 minutes and then at 116° C. for 3 minutes. The dried adhesivecoating was then stripped off the release liner and placed in a glassbottle. The foregoing procedure results in a reduction of the amount ofany residual monomer in the adhesive copolymer.

Preparative Method 3

Preparation of Isooctyl Acrylate:Acrylamide:Vinyl Acetate (75:5:20)Copolymer

The procedure of Preparative Method 1 above acrylate, 8.0 g acrylamide,32.0 g vinyl acetate, 0.32 g benzoyl peroxide, 216.0 g ethyl acetate and24.0 g methyl alcohol. The resulting polymer was diluted with the ethylacetate/methyl alcohol mixture to 21.52% solids. The adhesive polymerhad a measured inherent viscosity of 1.40 dl/g in ethyl acetate at aconcentration of 0.15 g/dl. Its Brookfield viscosity was 2,300centipoise.

Preparative Method 4

Preparation of Isooctyl Acrylate Acrylamide:Vinyl Acetate (75:5:20)Copolymer

A master batch was prepared by combining 621.0 g of isooctyl acrylate,41.4 g of acrylamide, 165.6 g of vinyl acetate, 1.656 g of2,2′-azobis(2,4-dimethylpentanenitrile) (available from the DuPontCompany as Vazo™52), 884.52 g of ethyl acetate and 87.48 g of methanol.A 400 g portion of the resulting solution was placed in an amber quartbottle. The bottle was purged for two minutes with nitrogen at a flowrate of one liter per minute. The bottle was sealed and placed in arotating water bath at 45° C. for twenty-four hours to effectessentially complete polymerization. The copolymer was diluted with 250g of ethyl acetate/methanol (90/10) to 26.05% solids and had a measuredinherent viscosity of 1.27 dl/g in ethyl acetate at a concentration of0.15 g/dl. Its Brookfield viscosity was 5580 centipoise.

Example I

A cream according to the present invention is prepared from thefollowing ingredients:

% by Weight Amount Oil Phase 1-isobutyl-1H-imidazo 1.0 40.0 g[4,5-c]-quinolin-4-amine Isostearic acid 10.0 400.0 g Benzyl alcohol 2.080.0 g Cetyl alcohol 2.2 88.0 g Stearyl alcohol 3.1 124.0 g Polysorbate60 2.55 102.0 g Sorbitan monostearate 0.45 18.0 g Aqueous Phase Glycerin2.0 80.0 g Methylparaben 0.2 8.0 g Propylparaben 0.02 0.8 g Purifiedwater 76.48 3059.2 g

The materials listed above were combined according to the followingprocedure: The glycerin, methylparaben, propylparaben and water wereweighed into a 4 liter glass beaker then heated on a hot plate withstirring until the parabens isostearic acid and1-isobutyl-1H-imidazo[4,5-c]-quinolin-4-amine were weighed into an 8liter stainless steel beaker and heated on a hot plate until the aminewas in solution (the temperature reached 69° C.). The benzyl alcohol,cetyl alcohol, stearyl alcohol, polysorbate 60 and sorbitan monostearatewere added to the isostearic acid solution and heated on a hot plateuntil all material was dissolved (the temperature reached 75° C.). Withboth phases at approximately the same temperature (65°-75° C.), thewater phase was added to the oil phase. The mixture was mixed with ahomogenizer for 13 minutes then put into a cool water bath and mixedwith a 3 inch propeller for 40 minutes (the temperature was 29° C.). Theresulting cream was placed in glass jars.

Examples 2-9

Using the general method of Example 1, the cream formulations shown inTables 1 and 2 are prepared.

TABLE 1 % by Weight Example Example Example Example 2 3 4 5 Oil Phase1-isobutyl-1H-imidazo- 1.0 1.0 1.0 1.0 [4,5-c]quinolin-4-amineIsostearic acid 10.0 10.0 5.0 5.0 Benzyl alcohol 2.0 Cetyl alcohol 1.7Stearyl alcohol 2.3 Cetearyl alcohol 6.0 6.0 6.0 Polysorbate 60 2.552.55 2.55 2.55 Sorbitan monostearate 0.45 0.45 0.45 0.45 Brij ™ 30^(a)10.0 AqueousPhase Glycerin 2.0 2.0 2.0 2.0 Methylparaben 0.2 0.2 0.2 0.2Propylparaben 0.02 0.02 0.02 0.02 Purified water 77.78 77.78 82.78 72.78^(a)Brij ™ 30 (polyoxyethylene(4) lauryl ether) is available from ICIAmericas, Inc.

TABLE 2 % by Weight Example Example Example Example 6 7 8 9 Oil Phase1-isobutyl-1H-imidazo- 1.0 1.0 1.0 1.0 [4,5-c]quinolin-4-amineIsostearic acid 10.0 25.0 10.0 6.0 Benzyl alcohol 2.0 2.0 Cetyl alcohol2.2 1.7 Stearyl alcohol 3.1 2.3 Cetearyl alcohol 6.0 6.0 Polysorbate 602.55 3.4 2.55 2.55 Sorbitan monostearate 0.45 0.6 0.45 0.45 Brij ™30^(a) 10.0 Aqueous Phase Glycerin 2.0 2.0 2.0 2.0 Methylparaben 0.2 0.20.2 0.2 Propylparaben 0.02 0.02 0.02 0.02 Purified water 67.78 60.4879.78 79.78 ^(a)Brij ™ 30 (polyoxyethylene(4) lauryl ether) is availablefrom ICI Americas, Inc.

Example 10

A cream according to the present invention is prepared from thefollowing ingredients in the following Table 3:

TABLE 3 % by Weight Amount Oil Phase 1-isobutyl-H-1-imidazo 1.0 3.00 g[4,5-c]quinolin-4-amine Isostearic acid 5.0 15.0 g White petrolatum 15.045.0 g Light mineral oil 12.8 38.4 g Aluminum stearate 8.0 24.0 g Cetylalcohol 4.0 12.0 g Witconol ™ 14^(a) 3.0 9.00 g Acetylated lanolin 1.03.0 g Propylparaben 0.063 0.19 g Aqueous Phase Veegum ™ K^(b) 1.0 3.0 gMethylparaben 0.12 0.6 g Purified water 49.017 147.05 g ^(a)Witconol ™14 (polyglyceryl4 oleate) is available from Witco Chemical Corp.Organics Division ^(b)Veegum ™ K (colloidal magnesium aluminum silicate)is available from R. T. Vanderbilt Company Inc.

The materials listed above were combined according to the followingprocedure:

The 1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine and the isostearic acidwere weighed into a glass jar and heated with occasional stirring untilthe amine was dissolved (the temperature reached 68° C.). To thissolution was added, the petrolatum, mineral oil, aluminum stearate,cetyl alcohol, Witconol™ 14, acetylated lanoline and propylparaben. Themixture was heated to 75° C. In a separate beaker, the methylparaben andwater were combined and heated until the paraben dissolved (thetemperature reached 61° C.). The Veegum™ K was added to the aqueoussolution and heated at 75° C. for 30 minutes while mixing with ahomogenizer. With both phases at 75° C., the aqueous phase was slowlyadded to the oil phase while mixing with a homogenizer. Mixing wascontinued for 30 minutes while maintaining a temperature to about 80° C.The jar was then capped and the formulation was allowed to cool.

Example 11

An ointment according to the present invention is prepared from theingredients in the following Table 4:

TABLE 4 % by Weight Amount 1-isobutyl-1H-imidazo 1.0 0.20 g[4,5-c]quinolin-4-Amine Isostearic acid 5.0 1.00 g Mineral oil 12.8 2.56g White petrolatum 65.2 13.04 g Cetyl alcohol 4.0 0.80 g Acetylatedlanolin 1.0 0.20 g Witconol ™ 143.0 0.60 g Aluminum stearate 8.0 1.60 g

The materials listed above are combined according to the followingprocedure:

The 1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine and the isostearic acidwere placed in a glass jar and heated with stirring until the amine wasdissolved. The remaining ingredients were added and the resultingmixture was heated to 65° C. and then mixed while being allowed to coolto room temperature.

Example 12

Using the general procedure of Example 11 an ointment containing theingredients in the following Table 5 is prepared.

TABLE 5 % by Weight Amount 1-Isobutyl-1H-imidazo 1.0 0.20 g [4,5-c]quinol in-4-Amine Isostearic acid 6.0 1.20 g Polyethylene Glycol 40055.8 11.16 g Polyethylene Glycol 3350 32.6 6.52 g Stearyl alcohol 4.60.92 g

Examples 13-15

Creams of the present invention are prepared using the ingredients shownin Table 6. The Example 1 except that benzyl alcohol was used with theisostearic acid to dissolve the 1-isobutyl-1H-imidazo [4,5-c]quinolin-4-amine.

TABLE 6 Example 13 Example 14 Example 15 Amount % Amount % Amount % byWeight by Weight by Weight Oil Phase 1-isobutyl-1H-imidazo 50 5.0 4.85[4,5-c]quinolin-4-amine Isotearic acid 25.0 25.0 24.3 Benzyl alcohol 2.02.0 1.94 Cetyl alcohol 2.2 2.2 1.16 Stearyl alcohol 3.1 3.1 1.75Petrolatum 3.0 2.91 Polysorbate 60 3.4 3.4 4.13 Sorbitan monostearate0.6 0.6 0.73 Stearic acid Aqueous Phase Glycerin 2.0 2.0 1.94Methylparaben 0.2 0.2 0.19 Propylparaben 0.02 0.02 0.02

Example 16

A cream according to the present invention is prepared from theingredients in the following Table 7:

TABLE 7 % by Weight % by Weight Amount Amount Oil Phase1-isobutyl-1H-imidazo[4,5-c] 4.0 0.80 g quinolin-4-Amine Isostearic acid20.0 4.00 g Benzyl alcohol 2.0 0.40 g Cetyl alcohol 2.2 0.49 g Stearylalcohol 3.1 0.62 g Polysorbate 60 3.4 0.68 g Sorbitan monostearate 0.60.12 g Aqueous Phase 1-isobutyl-1H-imidazo [4,5-c] 1.0 0.2 gquinolin-4-amine Glycerin 2.0 0.4 g 85% Lactic acid 1.0 0.22 gMethylparaben 0.2 0.04 g Propylparaben 0.02 0.004 g Purified water 60.4812.0 g

The materials listed above are combined according to the followingprocedure: The isostearic acid and 0.8 g of1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine or1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine were combined in aglass jar and heated with stirring until the amine had dissolved. Theremaining oil phase ingredients were added to this solution and themixture was heated to about 70° C. The aqueous phase ingredients wereweighed into a separate beaker and heated with stirring until the amineand the parabens had dissolved. With both phases at about 70° C., thewater phase was added to the oil phase and mixed with a propeller untilthe mixture cooled to room temperature.

Example 17

A mixture of 5.9415 g of the 93:7 isooctyl acrylate:acrylamide adhesivecopolymer prepared in PREPARATIVE METHOD 2 above, 1.5126 g isostearicacid, 2.0075 g ethyl oleate, 0.3021 g glyceryl monolaurate, 0.29361-isobutyl-1H-imidazo [4,5-c]quinolin-4-amine (micronized) and 23.7 g of90:10 ethyl acetate:methanol was placed in a small glass jar. The jarwas placed on a horizontal shaker and shaken at room temperature forabout 13 hours. The formulation was coated at a thickness of 20 milsonto a 5 mil Daubert 164Z liner. The laminate was oven dried for 3minutes at 105° F., for 2 minutes at 185° F., and for 2 minutes at 210°F. The resulting adhesive coating contained 59.1 percent 93:7 isooctylacrylate:acylamide adhesive copolymer, 15.0 percent isostearic acid,20.0 percent ethyl oleate, 3.0 percent glyceryl monolaurate and 2.9percent 1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine. The material wasthen laminated with 3 mil low density polyethylene backing and die cutinto 2.056 cm.sup.2 patches.

Examples 18-20 Pressure-Sensitive Adhesive Coated Sheet MaterialsPrepared Using Unmicronized 1-isobutyl-1H-imidazo [4.5-c]quinolin-4-amine

Using the general method of Example 17 the formulations shown below areprepared. 1-Isobutyl-1H-imidazo[4,5-c]quinolin-4-amine or1-(2-methylpropyl)-1Himidazo[4,5-c]quinolin-4-amine that had been groundwith a mortar and pestle was used. The adhesive was the 93:7 isooctylacrylate:acrylamide copolymer prepared in Preparative Method 1 above.The solvent was 90:10 ethyl acetate:methanol. All formulations in thefollowing Table 8 were mixed at room temperature.

TABLE 8 Example 18 Example 19 Example 20 1-isobutyl-1H-imidazo 5.0 3.03.0 [4,5-c]quinolin-4-amine Ethyl oleate 5.1 5.0 8.0 Isostearic acid10.0 10.0 6.0 Oleic acid 20.0 20.0 13.0 Glyceryl monolaurate 1.5 1.5 1.5N,N-dimethyldodecylamine- 1.0 1.1 3.0 N-oxide Adhesive 57.4 59.3 65.4

Example 21

A formulation with the same components in the same proportions asExample 18 is prepared using a different method. The1-isobutyl-1H-imidazo[4,5-c]-quinolin-4-amine or1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine was combined withthe oleic and isostearic acids and shaken at 40° C. until there wascomplete dissolution of the1-isobutyl-1H-imidazo-[4,5-c]quinolin-4-amine or1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine. The remainingingredients were added and shaken a 40° C. for 72 hours. Patchesmeasuring 2.056 cm.sup.2 were prepared by the general method of Example17.

Example 22

A mixture of 2.4734 g 1-isobutyl-1H-imidazo[4,5-c]-quinolin-4-amine or1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine, 3.3315 gisostearic acid and 6.6763 g oleic acid is prepared. To 1.8738 g of theabove mixture was added 2.8750 g of the 93:7 isooctyl acrylate:acryamideadhesive copolymer prepared in Preparative Method 2 above, 0.2548 g ofethyl oleate, 0.0510 g N,N-dimethyldodecylamine-N-oxide, 0.0820 gglyceryl monolaurate (from Lauricidin, Inc.) and 14.0457 g of 90:10ethyl acetate/methanol. The above was shaken for 30 hours at roomtemperature on a horizontal shaker. Transdermal patches were thenprepared generally according to the procedures of Example 17.

Example 23

Topical Imiquimod Pharmaceutical Cream Formulations

Creams are prepared in accordance with the present invention using theingredients shown in this Example 23.

The materials listed below in this Example 23 are combined according tothe following procedure to make cream formulations in the followingTable 9 of this Example 23:

TABLE 9 Lower Dosage Strength Imiquimod Formulations Excipients % w/w %w/w % w/w % w/w % w/w % w/w Formulation 1 2 3 4 5 6 Fatty acid* 15.0015.00 15.00 20.00 15.00 20.00 Cetyl alcohol 2.20 2.20 2.20 2.20 2.202.20 Stearyl alcohol 3.10 3.10 3.10 3.10 3.10 3.10 White petrolatum 1.003.00 2.00 3.00 6.00 3.00 Polysorbate 60 3.40 3.40 3.40 3.40 3.00 3.00Sorbitan 0.60 0.60 0.60 0.60 1.00 1.00 Monostearate Glycerin 2.00 2.005.00 2.00 5.00 3.00 Xanthan gum 0.50 0.50 0.50 0.50 0.75 0.75 Purifiedwater 68.98 66.98 64.98 61.98 60.73 60.73 Benzyl alcohol 2.00 2.00 2.002.00 2.00 2.00 Methylparaben 0.20 0.20 0.20 0.20 0.20 0.20 Propylparaben0.02 0.02 0.02 0.02 0.02 0.02 Imiquimod 1.00 1.00 1.00 1.00 1.00 1.00Total 100.00 100.00 100.00 100.00 100.00 100.00 Excipients % w/w % w/w %w/w % w/w % w/w % w/w Formulation 7 8 9 10 11 12 Fatty acid* 15.00 15.0015.00 25.00 18.0 25.00 Cetyl alcohol 2.20 2.20 2.20 2.20 2.20 2.70Stearyl alcohol 3.10 3.10 3.10 3.10 3.10 3.80 White petrolatum 3.00 6.006.00 3.00 5.00 3.00 Polysorbate 60 3.40 3.40 3.00 3.40 3.00 3.40Sorbitan 0.60 0.60 1.00 0.50 1.00 0.60 Monostearate Glycerin 2.00 5.005.00 2.00 5.00 2.00 Xanthan gum 0.50 0.50 0.50 0.50 0.50 0.50 Purifiedwater 66.98 60.98 60.98 57.08 58.98 55.78 Benzyl alcohol 2.00 2.00 2.002.00 2.00 2.00 Methylparaben 0.20 0.20 0.20 0.20 0.20 0.20 Propylparaben0.02 0.02 0.02 0.02 0.02 0.02 Imiquimod 1.00 1.00 1.00 1.00 1.00 1.00Total 100.00 100.00 100.00 100.00 100.00 100.00 Excipients % w/w % w/w %w/w % w/w % w/w % w/w Formulation 13 14 15 16 17 18 Fatty acid* 25.0015.00 20.00 20.00 20.00 20.00 Cetyl alcohol 2.20 2.00 2.20 2.20 2.202.20 Stearyl alcohol 3.10 2.00 3.10 3.10 3.10 3.10 White petrolatum 3.003.40 5.00 3.00 5.00 3.00 Polysorbate 60 3.40 3.80 3.40 3.40 3.40 3.40Sorbitan 0.60 0.2 0.60 0.60 0.60 0.60 Monostearate Glycerin 2.00 3.002.00 5.00 5.00 2.00 Xanthan gum 1.00 0.30 0.50 0.50 0.50 0.50 Purifiedwater 56.48 67.08 59.98 58.98 56.98 61.98 Benzyl alcohol 2.00 2.00 2.002.00 2.00 2.00 Methylparaben 0.20 0.20 0.20 0.20 0.20 0.20 Propylparaben0.02 0.02 0.02 0.02 0.02 0.02 Imiquimod 1.00 1.00 1.00 1.00 1.00 1.00Total 100.00 100.00 100.00 100.00 100.00 100.00 Excipients % w/w % w/w %w/w % w/w % w/w % w/w Formulation 19 20 21 22 23 24 Fatty acid* 15.0015.00 15.00 20.00 15.00 20.00 Cetyl alcohol 2.20 2.20 2.20 2.20 2.202.20 Stearyl alcohol 3.10 3.10 3.10 3.10 3.10 3.10 White petrolatum 1.003.00 2.00 3.00 6.00 3.00 Polysorbate 60 3.40 3.40 3.40 3.40 3.00 3.00Sorbitan 0.60 0.60 0.60 0.60 1.00 1.00 Monostearate Glycerin 2.00 2.005.00 2.00 5.00 3.00 Xanthan gum 0.50 0.50 0.50 0.50 0.75 0.75 Purifiedwater 68.73 66.73 64.73 61.73 60.48 60.48 Benzyl alcohol 2.00 2.00 2.002.00 2.00 2.00 Methylparaben 0.20 0.20 0.20 0.20 0.20 0.20 Propylparaben0.02 0.02 0.02 0.02 0.02 0.02 Imiquimod 1.25 1.25 1.25 1.25 1.25 1.25Total 100.00 100.00 100.00 100.00 100.00 100.00 Excipients % w/w % w/w %w/w % w/w % w/w % w/w Formulation 25 26 27 28 29 30 Fatty acid* 15.0015.00 15.00 25.00 18.0 25.00 Cetyl alcohol 2.20 2.20 2.20 2.20 2.20 2.70Stearyl alcohol 3.10 3.10 3.10 3.10 3.10 3.80 White petrolatum 3.00 6.006.00 3.00 5.00 3.00 Polysorbate 60 3.40 3.40 3.00 3.40 3.00 3.40Sorbitan 0.60 0.60 1.00 0.50 1.00 0.60 Monostearate Glycerin 2.00 5.005.00 2.00 5.00 2.00 Xanthan gum 0.50 0.50 0.50 0.50 0.50 0.50 Purifiedwater 66.73 60.73 60.73 56.83 58.73 55.53 Benzyl alcohol 2.00 2.00 2.002.00 2.00 2.00 Methylparaben 0.20 0.20 0.20 0.20 0.20 0.20 Propylaraben0.02 0.02 0.02 0.02 0.02 0.02 Imiquimod 1.25 1.25 1.25 1.25 1.25 1.25Total 100.00 100.00 100.00 100.00 100.00 100.00 Excipients % w/w % w/w %w/w % w/w % w/w % w/w Formulation 31 32 33 34 35 36 Fatty acid* 25.0015.00 20.00 20.00 20.00 20.00 Cetyl alcohol 2.20 2.00 2.20 2.20 2.202.20 Stearyl alcohol 3.10 2.00 3.10 3.10 3.10 3.10 White petrolatum 3.003.40 5.00 3.00 5.00 3.00 Poly sorbate 60 3.40 3.80 3.40 3.40 3.40 3.40Sorbitan 0.60 0.2 0.60 0.60 0.60 0.60 Monostearate Glycerin 2.00 3.002.00 5.00 5.00 2.00 Xanthan gum 1.00 0.30 0.50 0.50 0.50 0.50 Purifiedwater 56.23 66.83 59.73 58.73 56.73 61.73 Benzyl alcohol 2.00 2.00 2.002.00 2.00 2.00 Methylparaben 0.20 0.20 0.20 0.20 0.20 0.20 Propylparaben0.02 0.02 0.02 0.02 0.02 0.02 Imiquimod 1.25 1.25 1.25 1.25 1.25 1.25Total 100.00 100.00 100.00 100.00 100.00 100.00 Excipients % w/w % w/w %w/w % w/w % w/w % w/w Formulation 37 38 39 40 41 42 Fatty acid* 15.0015.00 15.00 20.00 15.00 20.00 Cetyl alcohol 2.20 2.20 2.20 2.20 2.202.20 Stearyl alcohol 3.10 3.10 3.10 3.10 3.10 3.10 White petrolatum 1.003.00 2.00 3.00 6.00 3.00 Polysorbate 60 3.40 3.40 3.40 3.40 3.00 3.00Sorbitan 0.60 0.60 0.60 0.60 1.00 1.00 Monostearate Glycerin 2.00 2.005.00 2.00 5.00 3.00 Xanthan gum 0.50 0.50 0.50 0.50 0.75 0.75 Purifiedwater 68.48 66.48 64.48 61.48 60.23 60.23 Benzyl alcohol 2.00 2.00 2.002.00 2.00 2.00 Methylparaben 0.20 0.20 0.20 0.20 0.20 0.20 Propylparaben0.02 0.02 0.02 0.02 0.02 0.02 Imiquimod 1.50 1.50 1.50 1.50 1.50 1.50Total 100.00 100.00 100.00 100.00 100.00 100.00 Excipients % w/w % w/w %w/w % w/w % w/w % w/w Formulation 43 44 45 46 47 48 Fatty acid 15.0015.00 15.00 25.00 18.0 25.00 Cetyl alcohol 2.20 2.20 2.20 2.20 2.20 2.70Stearyl alcohol 3.10 3.10 3.10 3.10 3.10 3.80 White petrolatum 3.00 6.006.00 3.00 5.00 3.00 Polysorbate 60 3.40 3.40 3.00 3.40 3.00 3.40Sorbitan 0.60 0.60 1.00 0.50 1.00 0.60 Monostearate Glycerin 2.00 5.005.00 2.00 5.00 2.00 Xanthan gum 0.50 0.50 0.50 0.50 0.50 0.50 Purifiedwater 66.48 60.48 60.48 56.58 58.48 55.28 Benzyl alcohol 2.00 2.00 2.002.00 2.00 2.00 Methylparaben 0.20 0.20 0.20 0.20 0.20 0.20 Propylparaben0.02 0.02 0.02 0.02 0.02 0.02 Imiquimod 1.50 1.50 1.50 1.50 1.50 1.50Total 100.00 100.00 100.00 100.00 100.00 100.00 Excipients % w/w % w/w %w/w % w/w % w/w % w/w Formulation 49 50 51 52 53 54 Fatty acid* 25.0015.00 20.00 20.00 20.00 20.00 Cetyl alcohol 2.20 2.00 2.20 2.20 2.202.20 Stearyl alcohol 3.10 2.00 3.10 3.10 3.10 3.10 White petrolatum 3.003.40 5.00 3.00 5.00 3.00 Polysorbate 60 3.40 3.80 3.40 3.40 3.40 3.40Sorbitan 0.60 0.2 0.60 0.60 0.60 0.60 Monostearate Glycerin 2.00 3.002.00 5.00 5.00 2.00 Xanthan gum 1.00 0.30 0.50 0.50 0.50 0.50 Purifiedwater 55.98 66.58 59.48 58.48 56.48 61.48 Benzyl alcohol 2.00 2.00 2.002.00 2.00 2.00 Methylparaben 0.20 0.20 0.20 0.20 0.20 0.20 Propylparaben0.02 0.02 0.02 0.02 0.02 0.02 Imiquimod 1.50 1.50 1.50 1.50 1.50 1.50Total 100.00 100.00 100.00 100.00 100.00 100.00 Excipients % w/w % w/w %w/w % w/w % w/w % w/w Formulation 55 56 57 58 59 60 Fatty acid* 15.0015.00 15.00 20.00 15.00 20.00 Cetyl alcohol 2.20 2.20 2.20 2.20 2.202.20 Stearyl alcohol 3.10 3.10 3.10 3.10 3.10 3.10 White petrolatum 1.003.00 2.00 1.00 6.00 3.00 Polysorbate 60 3.40 3.40 3.40 3.40 3.00 3.00Sorbitan 0.60 0.60 0.60 0.60 1.00 1.00 Monostearate Glycerin 2.00 2.005.00 2.00 5.00 3.00 Xanthan gum 0.50 0.50 0.50 0.50 0.75 0.75 Purifiedwater 68.23 66.23 64.23 61.23 59.98 59.98 Benzyl alcohol 2.00 2.00 2.002.00 2.00 2.00 Methylparaben 0.20 0.20 0.20 0.20 0.20 0.20 Propylparaben0.02 0.02 0.02 0.02 0.02 0.02 Imiquimod 1.75 1.75 1.75 1.75 1.75 1.75Total 100.00 100.00 100.00 100.00 100.00 100.00 Excipients % w/w % w/w %w/w % w/w % w/w % w/w Formulation 61 62 63 64 65 66 Fatty acid* 15.0015.00 15.00 25.00 18.0 25.00 Cetyl alcohol 2.20 2.20 2.20 2.20 2.20 2.70Stearyl alcohol 3.10 3.10 3.10 3.10 3.10 3.80 White petrolatum 3.00 6.006.00 3.00 5.00 3.00 Polysorbate 60 3.40 3.40 3.00 3.40 3.00 3.40Sorbitan 0.60 0.60 1.00 0.50 1.00 0.60 Monostearate Glycerin 2.00 5.005.00 2.00 5.00 2.00 Xanthan gum 0.50 0.50 0.50 0.50 0.50 0.50 Purifiedwater 66.23 60.23 60.23 56.33 58.23 55.03 Benzyl alcohol 2.00 2.00 2.002.00 2.00 2.00 Methylparaben 0.20 0.20 0.20 0.20 0.20 0.20 Propylparaben0.02 0.02 0.02 0.02 0.02 0.02 Imiquimod 1.75 1.75 1.75 1.75 1.75 1.75Total 100.00 100.00 100.00 100.00 100.00 100.00 Excipients % w/w % w/w %w/w % w/w % w/w % w/w Formulation 67 68 69 70 71 72 Fatty acid* 25.0015.00 20.00 20.00 20.00 20.00 Cetyl alcohol 2.20 2.00 2.20 2.20 2.202.20 Stearyl alcohol 3.10 2.00 3.10 3.10 3.10 3.10 White petrolatum 3.003.40 5.00 3.00 5.00 3.00 Polysorbate 60 3.40 3.80 3.40 3.40 3.40 3.40Sorbitan 0.60 0.2 0.60 0.60 0.60 0.60 Monostearate Glycerin 2.00 3.002.00 5.00 5.00 2.00 Xanthan gum 1.00 0.30 0.50 0.50 0.50 0.50 Purifiedwater 55.73 66.33 59.23 58.23 56.23 61.23 Benzyl alcohol 2.00 2.00 2.002.00 2.00 2.00 Methylparaben 0.20 0.20 0.20 0.20 0.20 0.20 Propylparaben0.02 0.02 0.02 0.02 0.02 0.02 Imiquimod 1.75 1.75 1.75 1.75 1.75 1.75Total 100.00 100.00 100.00 100.00 100.00 100.00 Excipients % w/w % w/w %w/w % w/w % w/w % w/w Formulation 73 74 75 76 77 78 Fatty acid* 10.0012.50 25.00 10.00 15.00 20.00 Cetyl alcohol 2.20 2.20 2.70 4.00 4.002.20 Stearyl alcohol 3.10 3.10 3.80 2.00 2.00 3.10 White petrolatum 5.005.00 3.00 3.40 2.80 3.00 Polysorbate 60 3.40 3.40 3.40 3.80 3.00 3.00Sorbitan 0.60 0.60 0.60 1.00 1.00 1.00 Monostearate Glycerin 5.00 5.002.00 1.00 3.00 3.00 Xanthan gum 0.50 0.50 0.50 0.30 0.70 0.75 Purifiedwater 65.98 63.48 54.78 70.28 64.28 59.73 Benzyl alcohol 2.00 2.00 2.002.00 2.00 2.00 Methylparaben 0.20 0.20 0.20 0.20 0.20 0.20 Propylparaben0.02 0.02 0.02 0.02 0.02 0.02 Imiquimod 2.00 2.00 2.00 2.00 2.00 2.00Total 100.00 100.00 100.00 100.00 100.00 100.00 Excipients % w/w % w/w %w/w % w/w % w/w % w/w Formulation 79 80 81 82 83 84 Fatty acid* 10.0012.50 25.00 10.00 15.00 25.00 Cetyl alcohol 2.20 2.20 2.70 4.00 4.002.70 Stearyl alcohol 3.10 3.10 3.80 2.00 2.00 3.80 White petrolatum 5.005.00 3.00 3.40 2.80 3.00 Polysorbate 60 3.40 3.40 3.40 3.80 3.00 3.40Sorbitan 0.60 0.60 0.60 1.00 1.00 0.60 Monostearate Glycerin 5.00 5.002.00 1.00 3.00 2.00 Xanthan gum 0.50 0.50 0.50 0.30 0.70 0.50 Purifiedwater 65.98 63.48 54.78 70.28 64.28 54.78 Benzyl alcohol 2.00 2.00 2.002.00 2.00 2.00 Methylparaben 0.20 0.20 0.20 0.20 0.20 0.20 Propylparaben0.02 0.02 0.02 0.02 0.02 0.02 Imiquimod 2.00 2.00 2.00 2.00 2.00 2.00Total 100.00 100.00 100.00 100.00 100.00 100.00 Excipients % w/w % w/w %w/w % w/w % w/w % w/w Formulation 85 86 87 88 89 90 Fatty acid* 25.0015.00 20.00 20.00 20.00 20.0 Cetyl alcohol 2.20 2.00 2.20 2.20 2.20 2.20Stearyl alcohol 3.10 2.00 3.10 3.10 3.10 3.10 White petrolatum 3.00 3.405.00 3.00 5.00 3.00 Polysorbate 60 3.40 3.80 3.40 3.40 3.40 3.40Sorbitan 0.60 0.2 0.60 0.60 0.60 0.60 Monostearate Glycerin 2.00 3.002.00 5.00 5.00 2.00 Xanthan gum 1.00 0.30 0.50 0.50 0.50 0.50 Purifiedwater 55.48 66.08 58.98 57.98 55.98 60.98 Benzyl alcohol 2.00 2.00 2.002.00 2.00 2.00 Methylparaben 0.20 0.20 0.20 0.20 0.20 0.20 Propylparaben0.02 0.02 0.02 0.02 0.02 0.02 Imiquimod 2.00 2.00 2.00 2.00 2.00 2.00Total 100.00 100.00 100.00 100.00 100.00 100.00 Excipients % w/w % w/w %w/w % w/w % w/w % w/w Formulation 91 92 93 94 95 96 Fattty acid* 15.0012.50 25.00 15.00 10.00 20.00 Cetyl alcohol 2.20 2.20 2.20 2.00 2.002.20 Stearyl alcohol 3.10 3.10 3.10 2.00 2.40 3.10 White petrolatum 6.005.00 3.00 3.40 2.80 3.00 Polysorbate 60 3.00 3.00 3.40 3.80 3.80 3.00Sorbitan 1.00 1.00 0.60 0.20 1.00 1.00 Monostearate Glycerin 5.00 5.002.00 3.00 3.00 3.00 Xanthan gum 1.00 0.50 1.00 0.30 0.30 0.75 Purifiedwater 60.23 63.23 55.23 66.83 70.23 59.48 Benzyl alcohol 1.00 2.00 2.001.00 2.00 2.00 Methylparaben 0.20 0.20 0.20 0.20 0.20 0.20 Propylparaben0.02 0.02 0.02 0.02 0.02 0.02 Imiquimod 2.25 2.25 2.25 2.25 2.25 2.25Total 100.00 100.00 100.00 100.00 100.00 100.00 Excipients % w/w % w/w %w/w % w/w % w/w % w/w Formulation 97 98 99 100 101 102 Fatty acid* 15.0012.50 25.00 15.00 10.00 25.00 Cetyl alcohol 2.20 2.20 2.20 2.00 2.002.70 Stearyl alcohol 3.10 3.10 3.10 2.00 2.40 3.80 White petrolatum 6.005.00 3.00 3.40 2.80 3.00 Polysorbate 60 3.00 3.00 3.40 3.80 3.80 3.40Sorbitan 1.00 1.00 0.60 0.20 1.00 0.60 Monostearate Glycerin 5.00 5.002.00 3.00 3.00 2.00 Xanthan gum 1.00 0.50 1.00 0.30 0.30 0.50 Purifiedwater 60.23 63.23 55.23 66.83 70.23 54.53 Benzyl alcohol 1.00 2.00 2.001.00 2.00 2.00 Methylparaben 0.20 0.20 0.20 0.20 0.20 0.20 Propylparaben0.02 0.02 0.02 0.02 0.02 0.02 Imiquimod 2.25 2.25 2.25 2.25 2.25 2.25Total 100.00 100.00 100.00 100.00 100.00 100.00 Excipients % w/w % w/w %w/w % w/w % w/w % w/w Formulation 103 104 105 106 107 108 Fatty acid*25.00 15.00 20.00 20.00 20.00 20.00 Cetyl alcohol 2.20 2.00 2.20 2.202.20 2.20 Stearyl alcohol 3.10 2.00 3.10 3.10 3.10 3.10 White petrolatum3.00 3.40 5.00 3.00 5.00 3.00 Polysorbate 60 3.40 3.80 3.40 3.40 3.403.40 Sorbitan 0.60 0.2 0.60 0.60 0.60 0.60 Monostearate Glycerin 2.003.00 2.00 5.00 5.00 2.00 Xanthan gum 1.00 0.30 0.50 0.50 0.50 0.50Purified water 55.23 65.83 58.73 57.73 55.73 60.73 Benzyl alcohol 2.002.00 2.00 2.00 2.00 2.00 Methylparaben 0.20 0.20 0.20 0.20 0.20 0.20Propylparaben 0.02 0.02 0.02 0.02 0.02 0.02 Imiquimod 2.25 2.25 2.252.25 2.25 2.25 Total 100.00 100.00 100.00 100.00 100.00 100.00Excipients % w/w % w/w % w/w % w/w % w/w % w/w Formulation 109 110 111112 113 114 Fatty acid* 15.00 15.00 15.00 20.00 15.00 20.00 Cetylalcohol 2.20 2.20 2.20 2.20 2.20 2.20 Stearyl alcohol 3.10 3.10 3.103.10 3.10 3.10 White petrolatum 2.50 3.00 2.00 3.00 6.00 3.00Polysorbate 60 3.40 3.40 3.40 3.40 3.00 3.00 Sorbitan 0.60 0.60 0.600.60 1.00 1.00 Monostearate Glycerin 2.00 2.00 5.00 2.00 5.00 3.00Xanthan gum 0.50 0.50 0.50 0.50 0.75 0.75 Purified water 65.98 65.4863.48 60.48 59.23 59.23 Benzyl alcohol 2.00 2.00 2.00 2.00 2.00 2.00Methylparaben 0.20 0.20 0.20 0.20 0.20 0.20 Propylparaben 0.02 0.02 0.020.02 0.02 0.02 Imiquimod 2.50 2.50 2.50 2.50 2.50 2.50 Total 100.00100.00 100.00 00.00 100.00 100.00 Excipients % w/w % w/w % w/w % w/w %w/w % w/w Formulation 115 116 117 118 119 120 Fatty acid* 15.00 15.0015.00 25.00 18.0 25.00 Cetyl alcohol 2.20 2.20 2.20 2.20 2.20 2.70Stearyl alcohol 3.10 3.10 3.10 3.10 3.10 3.80 White petrolatum 3.00 6.006.00 3.00 5.00 3.00 Polysorbate 60 3.40 3.40 3.00 3.40 3.00 3.40Sorbitan 0.60 0.60 1.00 0.50 1.00 0.60 Monostearate Glycerin 2.00 5.005.00 2.00 5.00 2.00 Xanthan gum 0.50 0.50 0.50 0.50 0.50 0.50 Purifiedwater 65.48 59.48 59.48 55.58 57.48 54.28 Benzyl alcohol 2.00 2.00 2.002.00 2.00 2.00 Methylparaben 0.20 0.20 0.20 0.20 0.20 0.20 Propylparaben0.02 0.02 0.02 0.02 0.02 0.02 Imiquimod 2.50 2.50 2.50 2.50 2.50 2.50Total 100.00 100.00 100.00 100.00 1100.00 100.00 Excipients % w/w % w/w% w/w % w/w % w/w % w/w Formulation 121 122 123 124 125 126 Fatty acid*25.00 15.00 20.00 20.00 20.00 20.00 Cetyl alcohol 2.20 2.00 2.20 2.202.20 2.20 Stearyl alcohol 3.10 2.00 3.10 3.10 3.10 3.10 White petrolatum3.00 3.40 5.00 3.00 5.00 3.00 Polysorbate 60 3.40 3.80 3.40 3.40 3.403.40 Sorbitan 0.60 0.2 0.60 0.60 0.60 0.60 Monostearate Glycerin 2.003.00 2.00 5.00 5.00 2.00 Xanthan gum 1.00 0.30 0.50 0.50 0.50 0.50Purified water 54.98 65.58 58.48 57.48 55.48 60.48 Benzyl alcohol 2.002.00 2.00 2.00 2.00 2.00 Methylparaben 0.20 0.20 0.20 0.20 0.20 0.20Propylparaben 0.02 0.02 0.02 0.02 0.02 0.02 Imiquimod 2.50 2.50 2.502.50 2.50 2.50 Total 100.00 100.00 100.00 100.00 00.00 100.00 Excipients% w/w % w/w % w/w % w/w % w/w % w/w Formulation 127 128 129 130 131 132Fatty acid* 15.00 18.00 15.00 20.00 12.50 20.00 Cetyl alcohol 2.00 2.002.00 2.00 2.20 2.20 Stearyl alcohol 2.00 2.00 2.40 2.40 3.10 3.10 Whitepetrolatum 3.40 2.80 3.40 2.80 5.00 3.00 Polysorbate 60 3.00 3.80 3.003.00 3.40 3.00 Sorbitan 1.00 1.00 0.20 0.20 0.60 1.00 MonostearateGlycerin 3.00 2.00 1.00 3.00 6.00 3.00 Xanthan gum 0.30 0.70 0.70 0.300.50 0.75 Purified water 65.08 62.48 67.08 61.08 61.48 58.73 Benzylalcohol 2.00 2.00 2.00 2.00 2.00 2.00 Methylparaben 0.20 0.20 0.20 0.200.20 0.20 Propylparaben 0.02 0.02 0.02 0.02 0.02 0.02 Imiquimod 3.003.00 3.00 3.00 3.00 3.00 Total 100.00 100.00 100.00 100.00 100.00 100.00Excipients % w/w % w/w % w/w % w/w % w/w % w/w Formulation 133 134 135136 137 138 Fatty acid* 15.00 18.00 15.00 20.00 12.50 25.00 Cetylalcohol 2.00 2.00 2.00 2.00 2.20 2.70 Stearyl alcohol 2.00 2.00 2.402.40 3.10 3.80 White petrolatum 3.40 2.80 3.40 2.80 5.00 3.00Polysorbate 60 3.00 3.80 3.00 3.00 3.40 3.40 Sorbitan 1.00 1.00 0.200.20 0.60 0.60 Monostearate Glycerin 3.00 2.00 1.00 3.00 6.00 2.00Xanthan gum 0.30 0.70 0.70 0.30 0.50 0.50 Purified water 65.08 62.4867.08 61.08 61.48 53.78 Benzyl alcohol 2.00 2.00 2.00 2.00 2.00 2.00Methylparaben 0.20 0.20 0.20 0.20 0.20 0.20 Propylparaben 0.02 0.02 0.020.02 0.02 0.02 Imiquimod 3.00 3.00 3.00 3.00 3.00 3.00 Total 100.00100.00 100.00 100.00 100.00 100.00 Excipients % w/w % w/w % w/w % w/w %w/w % w/w Formulation 139 140 141 142 143 144 Fatty acid* 25.00 15.0020.00 20.00 20.00 20.00 Cetyl alcohol 2.20 2.00 2.20 2.20 2.20 2.20Stearyl alcohol 3.10 2.00 3.10 3.10 3.10 3.10 White petrolatum 3.00 3.405.00 3.00 5.00 3.00 Polysorbate 60 3.40 3.80 3.40 3.40 3.40 3.40Sorbitan 0.60 0.2 0.60 0.60 0.60 0.60 Monostearate Glycerin 2.00 3.002.00 5.00 5.00 2.00 Xanthan gum 1.00 0.30 0.50 0.50 0.50 0.50 Purifiedwater 54.48 65.08 57.98 56.98 54.98 59.98 Benzyl alcohol 2.00 2.00 2.002.00 2.00 2.00 Methylparaben 0.20 0.20 0.20 0.20 0.20 0.20 Propylparaben0.02 0.02 0.02 0.02 0.02 0.02 Imiquimod 3.00 3.00 3.00 3.00 3.00 3.00Total 100.00 100.00 100.00 100.00 100.00 100.00 Excipients % w/w % w/w %w/w % w/w % w/w % w/w Formulation 145 146 147 148 149 150 Fatty acid*15.00 20.00 15.00 20.00 10.00 20.00 Cetyl alcohol 2.00 2.00 4.00 4.002.20 2.20 Stearyl alcohol 2.00 2.40 2.40 2.40 3.10 3.10 White petrolatum3.40 2.80 2.50 3.40 5.00 3.00 Polysorbate 60 3.00 3.00 3.00 3.80 3.403.00 Sorbitan 1.00 0.20 1.00 1.00 0.60 1.00 Monostearate Glycerin 3.003.00 1.00 3.00 5.00 3.00 Xanthan gum 0.30 0.30 0.30 0.70 0.50 0.75Purified water 64.83 60.83 65.33 57.23 64.73 58.48 Benzyl alcohol 2.002.00 2.00 1.00 2.00 2.00 Methylparaben 0.20 0.20 0.20 0.20 0.20 0.20Propylparaben 0.02 0.02 0.02 0.02 0.02 0.02 Imiquimod 3.25 3.25 3.253.25 3.25 3.25 Total 100.00 100.00 100.00 100.00 100.00 100.00Excipients % w/w % w/w % w/w % w/w % w/w % w/w Formulation 151 152 153154 155 156 Fatty acid* 15.00 20.00 15.00 20.00 10.00 25.00 Cetylalcohol 2.00 2.00 4.00 4.00 2.20 2.70 Steatyl alcohol 2.00 2.40 2.402.40 3.10 3.80 White petrolatum 3.40 2.80 2.50 3.40 5.00 3.00Polysorbate 60 3.00 3.00 3.00 3.80 3.40 3.40 Sorbitan 1.00 0.20 1.001.00 0.60 0.60 Monostearate Glycerin 3.00 3.00 1.00 3.00 5.00 2.00Xanthan gum 0.30 0.30 0.30 0.70 0.50 0.50 Purified water 64.83 60.8365.33 57.23 64.73 53.53 Benzyl alcohol 2.00 2.00 2.00 1.00 2.00 2.00Methylparaben 0.20 0.20 0.20 0.20 0.20 0.20 Propylparaben 0.02 0.02 0.020.02 0.02 0.02 Imiquimod 3.25 3.25 3.25 3.25 3.25 3.25 Total 100.00100.00 100.00 100.00 100.00 100.00 Excipients % w/w % w/w % w/w % w/w %w/w % w/w Formulation 157 158 159 160 161 162 Fatty acid* 25.00 15.0020.00 20.00 20.00 20.00 Cetyl alcohol 2.20 2.00 2.20 2.20 2.20 2.20Stearyl alcohol 3.10 2.00 3.10 3.10 3.10 3.10 White petrolatum 3.00 3.405.00 3.00 5.00 3.00 Polysorbate 60 3.40 3.80 3.40 3.40 3.40 3.40Sorbitan 0.60 0.2 0.60 0.60 0.60 0.60 Monostearate Glycerin 2.00 3.002.00 5.00 5.00 2.00 Xanthan gum 1.00 0.30 0.50 0.50 0.50 0.50 Purifiedwater 54.23 64.83 59.98 56.73 54.73 59.73 Benzyl alcohol 2.00 2.00 2.002.00 2.00 2.00 Methylparaben 0.20 0.20 0.20 0.20 0.20 0.20 Propylparaben0.02 0.02 0.02 0.02 0.02 0.02 Imiquimod 3.25 3.25 3.25 3.25 3.25 3.25Total 100.00 100.00 100.00 100.00 100.00 100.00 Excipients % w/w % w/w %w/w % w/w % w/w % w/w Formulation 163 164 165 166 167 168 Fatty acid*15.00 10.00 12.50 19.00 20.00 20.00 Cetyl alcohol 2.00 2.20 2.20 2.202.20 2.20 Stearyl alcohol 2.40 3.10 3.10 3.10 3.10 3.10 White petrolatum3.40 5.00 5.00 3.00 3.00 3.00 Polysorbate 60 3.00 3.40 4.00 3.40 3.403.00 Sorbitan 0.20 0.60 0.60 0.60 0.60 1.00 Monostearate Glycerin 1.004.00 5.00 2.00 6.00 3.00 Xanthan gum 0.70 0.50 0.50 0.50 0.50 0.75Purified water 66.58 65.48 61.38 60.48 56.48 58.23 Benzyl alcohol 2.002.00 2.00 2.00 1.00 2.00 Methylparaben 0.20 0.20 0.20 0.20 0.20 0.20Propylparaben 0.02 0.02 0.02 0.02 0.02 0.02 Imiquimod 3.50 3.50 3.503.50 3.50 3.50 Total 100.00 100.00 100.00 100.00 100.00 100.00Excipients % w/w % w/w % w/w % w/w % w/w % w/w Formulation 169 170 171172 173 174 Fatty acid* 15.00 10.00 12.50 19.00 20.00 25.00 Cetylalcohol 2.00 2.20 2.20 2.20 2.20 2.70 Stearyl alcohol 2.40 3.10 3.103.10 3.10 3.80 White petrolatum 3.40 5.00 5.00 3.00 3.00 3.00Polysorbate 60 3.00 3.40 4.00 3.40 3.40 3.40 Sorbitan 0.20 0.60 0.600.60 0.60 0.60 Monostearate Glycerin 1.00 4.00 5.00 2.00 6.00 2.00Xanthan gum 0.70 0.50 0.50 0.50 0.50 0.50 Purified water 66.58 65.4861.38 60.48 56.48 53.28 Benzyl alcohol 2.00 2.00 2.00 2.00 1.00 2.00Methylparaben 0.20 0.20 0.20 0.20 0.20 0.20 Propylparaben 0.02 0.02 0.020.02 0.02 0.02 Imiquimod 3.50 3.50 3.50 3.50 3.50 3.50 Total 100.00100.00 100.00 100.00 100.00 100.00 Excipients % w/w % w/w % w/w % w/w %w/w % w/w Formulation 175 176 177 178 179 180 Fatty acid* 25.00 15.0020.00 20.00 20.00 20.00 Cetyl alcohol 2.20 2.00 2.20 2.20 2.20 2.20Stearyl alcohol 3.10 2.00 3.10 3.10 3.10 3.10 White petrolatum 3.00 3.405.00 3.00 5.00 3.00 Polysorbate 60 3.40 3.80 3.40 3.40 3.40 3.40Sorbitan 0.60 0.2 0.60 0.60 0.60 0.60 Monostearate Glycerin 2.00 3.002.00 5.00 5.00 2.00 Xanthan gum 1.00 0.30 0.50 0.50 0.50 0.50 Purifiedwater 53.98 64.58 57.48 56.48 54.48 59.48 Benzyl alcohol 2.00 2.00 2.002.00 2.00 2.00 Methylparaben 0.20 0.20 0.20 0.20 0.20 0.20 Propylparaben0.02 0.02 0.02 0.02 0.02 0.02 Imiquimod 3.50 3.50 3.50 3.50 3.50 3.50Total 100.00 100.00 100.00 100.00 100.00 100.00 Excipients % w/w % w/w %w/w % w/w % w/w % w/w Formulation 181 182 183 184 185 186 Fatty acid*20.00 20.00 25.00 18.75 20.00 21.2 Cetyl alcohol 4.00 2.20 2.20 2.202.20 2.20 Stearyl alcohol 2.40 3.10 3.10 3.10 3.10 3.10 White petrolatum2.80 3.00 3.00 5.00 5.00 3.75 Polysorbate 60 3.00 3.40 3.40 3.00 3.403.40 Sorbitan 1.00 0.60 0.60 1.00 0.60 0.60 Monostearate Glycerin 1.002.00 2.00 5.00 5.00 5.00 Xanthan gum 0.30 0.50 0.50 0.05 0.50 0.50Purified water 64.53 59.23 54.23 55.48 54.23 54.23 Benzyl alcohol 2.002.00 2.00 2.00 2.00 2.00 Methylparaben 0.20 0.20 0.20 0.20 0.20 0.20Propylparaben 0.02 0.02 0.02 0.02 0.02 0.02 Imiquimod 3.75 3.75 3.753.75 3.75 3.75 Total 100.00 100.00 100.00 100.00 100.00 100.00Excipients % w/w % w/w % w/w % w/w % w/w % w/w Formulation 187 188 189190 191 192 Fatty acid* 20.00 20.00 20.00 25.00 18.75 25.00 Cetylalcohol 2.20 2.20 2.20 2.20 2.20 2.70 Stearyl alcohol 3.10 3.10 3.103.10 3.10 3.80 White petrolatum 3.00 6.00 6.00 3.00 5.00 3.00Polysorbate 60 3.40 3.40 3.00 3.40 3.00 3.40 Sorbitan 0.60 0.60 1.000.50 1.00 0.60 Monostearate Glycerin 2.00 5.00 5.00 2.00 5.00 2.00Xanthan gum 0.50 0.50 0.50 0.50 0.50 0.50 Purified water 59.23 53.2353.23 54.33 55.48 53.03 Benzyl alcohol 2.00 2.00 2.00 2.00 2.00 2.00Methylparaben 0.20 0.20 0.20 0.20 0.20 0.20 Propylparaben 0.02 0.02 0.020.02 0.02 0.02 Imiquimod 3.75 3.75 3.75 3.75 3.75 3.75 Total 100.00100.00 100.00 100.00 100.00 100.00 Excipients % w/w % w/w % w/w % w/w %w/w % w/w Formulation 193 194 195 196 197 198 Fatty acid* 25.00 20.0020.00 20.00 20.00 21.00 Cetyl alcohol 2.20 4.00 2.20 2.20 2.20 2.20Stearyl alcohol 3.10 2.40 3.10 3.10 3.10 3.10 White petrolatum 3.00 3.405.00 3.00 5.00 5.00 Polysorbate 60 3.40 3.80 3.40 3.40 3.40 3.40Sorbitan 0.60 1.00 0.60 0.60 0.60 0.60 Monostearate Glycerin 2.00 3.002.00 5.00 5.00 5.00 Xanthan gum 1.00 0.70 0.50 0.50 0.50 0.50 Purifiedwater 53.73 55.73 57.23 56.23 54.23 53.23 Benzyl alcohol 2.00 2.00 2.002.00 2.00 2.00 Methylparaben 0.20 0.20 0.20 0.20 0.20 0.20 Propylparaben0.02 0.02 0.02 0.02 0.02 0.02 Imiquimod 3.75 3.75 3.75 3.75 3.75 3.7Total 100.00 100.00 100.00 100.00 100.00 100.00 Excipients % w/w % w/w %w/w % w/w % w/w % w/w Formulation 199 200 201 202 203 204 Fatty acid*20.00 25.00 22.50 20.00 20.00 22.50 Cetyl alcohol 2.20 2.70 2.20 4.002.20 2.20 Stearyl alcohol 3.10 3.80 3.10 2.40 3.10 3.10 White petrolatum6.00 3.00 3.00 3.40 5.00 4.00 Polysorbate 60 3.00 3.40 3.40 3.80 3.403.40 Sorbitan 1.00 0.60 0.60 1.00 0.60 0.60 Monostearate Glycerin 5.002.00 2.00 3.00 2.00 2.00 Xanthan gum 0.50 0.50 1.00 0.70 0.50 0.50Purified water 52.98 52.78 55.98 55.48 56.98 55.48 Benzyl alcohol 2.002.00 2.00 2.00 2.00 2.00 Methylparaben 0.20 0.20 0.20 0.20 0.20 0.20Propylparaben 0.02 0.02 0.02 0.02 0.02 0.02 Imiquimod 4.00 4.00 4.004.00 4.00 4.00 Total 100.00 100.00 100.00 100.00 100.00 100.00Excipients % w/w % w/w % w/w % w/w % w/w % w/w Formulation 205 206 207208 209 210 Fatty acid* 20.00 25.00 22.50 20.00 20.00 22.50 Cetylalcohol 2.20 2.70 2.20 4.00 2.20 2.20 Stearyl alcohol 3.10 3.80 3.102.40 3.10 3.10 White petrolatum 6.00 3.00 3.00 3.40 5.00 4.00Polysorbate 60 3.00 3.40 3.40 3.80 3.40 3.40 Sorbitan 1.00 0.60 0.601.00 0.60 0.60 Monostearate Glycerin 5.00 2.00 2.00 3.00 2.00 2.00Xanthan gum 0.50 0.50 1.00 0.70 0.50 0.50 Purified water 52.98 52.7855.98 55.48 56.98 55.48 Benzyl alcohol 2.00 2.00 2.00 2.00 2.00 2.00Methylparaben 0.20 0.20 0.20 0.20 0.20 0.20 Propylbaraben 0.02 0.02 0.020.02 0.02 0.02 Imiquimod 4.00 4.00 4.00 4.00 4.00 4.00 Total 100.00100.00 100.00 100.00 100.00 100.00 Excipients % w/w % w/w % w/w % w/w %w/w % w/w Formulation 211 212 213 214 215 216 Fatty acid* 25.00 15.0020.00 20.00 20.00 20.00 Cetyl alcohol 2.20 2.00 2.20 2.20 2.20 2.20Stearyl alcohol 3.10 2.00 3.10 3.10 3.10 3.10 White petrolatum 3.00 3.405.00 3.00 5.00 3.00 Polysorbate 60 3.40 3.80 3.40 3.40 3.40 3.40Sorbitan 0.60 0.2 0.60 0.60 0.60 0.60 Monostearate Glycerin 2.00 3.002.00 5.00 5.00 2.00 Xanthan gum 1.00 0.30 0.50 0.50 0.50 0.50 Purifiedwater 53.48 64.08 56.98 55.98 53.98 58.98 Benzyl alcohol 2.00 2.00 2.002.00 2.00 2.00 Methylparaben 0.20 0.20 0.20 0.20 0.20 0.20 Propylparaben0.02 0.02 0.02 0.02 0.02 0.02 Imiquimod 4.00 4.00 4.00 4.00 4.00 4.00Total 100.00 100.00 100.00 100.00 100.00 100.00 Excipient % w/w % w/w %w/w % w/w % w/w % w/w Formulation 217 218 219 220 221 222 Fatty acid*15.00 15.00 15.00 20.00 15.00 20.00 Cetyl alcohol 2.20 2.20 2.20 2.202.20 2.20 Stearyl alcohol 3.10 3.10 3.10 3.10 3.10 3.10 White petrolatum1.00 3.00 2.00 3.00 6.00 3.00 Polysorbate 60 3.40 3.40 3.40 3.40 3.003.00 Sorbitan 0.60 0.60 0.60 0.60 1.00 1.00 Monostearate Glycerin 2.002.00 5.00 2.00 5.00 3.00 Xanthan gum 0.50 0.50 0.50 0.50 0.75 0.75Purified water 65.73 63.73 61.73 58.73 57.48 57.48 Benzyl alcohol 2.002.00 2.00 2.00 2.00 2.00 Methylparaben 0.20 0.20 0.20 0.20 0.20 0.20Propyparaben 0.02 0.02 0.02 0.02 0.02 0.02 Imiquimod 4.25 4.25 4.25 4.254.25 4.25 Total 100.00 100.00 100.00 100.00 100.00 100.00 Excipients %w/w % w/w % w/w % w/w % w/w % w/w Formulation 223 224 225 226 227 228Fatty acid* 15.00 15.00 15.00 25.00 18.0 25.00 Cetyl alcohol 2.20 2.202.20 2.20 2.20 2.70 Stearyl alcohol 3.10 3.10 3.10 3.10 3.10 3.80 Whitepetrolatum 3.00 6.00 6.00 3.00 5.00 3.00 Polysorbate 60 3.40 3.40 3.003.40 3.00 3.40 Sorbitan 0.60 0.60 1.00 0.50 1.00 0.60 MonostearateGlycerin 2.00 5.00 5.00 2.00 5.00 2.00 Xanthan gum 0.50 0.50 0.50 0.500.50 0.50 Purified water 63.73 57.73 57.73 53.83 55.73 52.53 Benzylalcohol 2.00 2.00 2.00 2.00 2.00 2.00 Methylparaben 0.20 0.20 0.20 0.200.20 0.20 Propylparaben 0.02 0.02 0.02 0.02 0.02 0.02 Imiquimod 4.254.25 4.25 4.25 4.25 4.25 Total 100.00 100.00 100.00 100.00 100.00 100.00Excipients % w/w % w/w % w/w % w/w % w/w % w/w Formulation 229 230 231232 233 234 Fatty acid* 25.00 15.00 20.00 20.00 20.0 20.00 Cetyl alcohol2.20 2.00 2.20 2.20 2.20 2.20 Stearyl alcohol 3.10 2.00 3.10 3.10 3.103.10 White petrolatum 3.00 3.40 5.00 3.00 5.00 3.00 Polysorbate 60 3.403.80 3.40 3.40 3.40 3.40 Sorbitan 0.60 0.20 0.60 0.60 0.60 0.60Monostearate Glycerin 2.00 3.00 2.00 5.00 5.00 2.00 Xanthan gum 1.000.30 0.50 0.50 0.50 0.50 Purified water 53.23 63.83 56.73 55.73 53.7358.73 Benzyl alcohol 2.00 2.00 2.00 2.00 2.00 2.00 Methylparaben 0.200.20 0.20 0.20 0.20 0.20 Propylparaben 0.02 0.02 0.02 0.02 0.02 0.02Imiquimod 4.25 4.25 4.25 4.25 4.25 4.25 Total 100.00 100.00 100.00100.00 100.00 100.00 *The Fatty acid referenced in this Table 9 can be,for example, linoleic acid (la), stearic acid (sa), palmitic acid (pa),isostearic acid (isa), unrefined oleic acid, (uoa), refined oleic acid,such as super refined oleic acid (roa), or mixtures thereof.

The work area, all vessels and equipment is initially cleaned prior tocommencing manufacture. A 2 L glass container and paddle stirrer bladeare placed onto a balance and the weight is recorded. The paddle is thenremoved from the vessel. The isostearic acid and benzyl alcohol areweighed directly into the 2 L glass container. The imiquimod is thenweighed into the 2 L glass container and a spatula is used to ensure theimiquimod is wetted with the isostearic acid and benzyl alcohol mixture.The 2 L container is then heated in a water bath to about 55±5° C. whilestirring with a Heidolph mixer (Note: aluminum foil is placed around thetop of the vessel and the paddle for the mixer, to limit evaporation).The solution is visually inspected to confirm the imiquimod has fullydissolved prior to mixing with cetyl alcohol, stearyl alcohol, whitepetrolatum, polysorbate 60 and sorbitan monostearate. Cetyl alcohol,stearyl alcohol, white petrolatum, polysorbate 60 and sorbitanmonostearate are then weighed directly into the 2 L container and mixingis continued at about 55±5° C. until the oil phase is completely insolution. Separately, about 2 L of water are placed into a beaker andheated to 55±5° C. while stirring with a magnetic follower. Briefly,about 500 ml of the heated water is transferred into a 1 L beaker andplaced into the water bath maintained at about 55±f 5° C. Half of theamount of glycerin required for the final formulation is then weighedinto the beaker along with the total amount of methylparaben andpropylparaben to the water (where both methyl and propyl paraben areweighed into weighing boats first, a pipette is used to remove a portionof the heated water to wash out the weighing boats to ensure totaltransfer of both the propyl- and methylparaben into the aqueous phase).The mixture is continuously stirred at about 55±5° C. (this is theaqueous phase). The remaining glycerin is then added to a 28 ml vial andthe xanthan gum is added and mixed using a small overhead mixer(1KA®-Werke Lab Egg) with paddle attachment for about 10 min. Theglycerin and xanthan mixture are then added slowly into the vortex ofthe aqueous phase, and a further aliquot of about 20 ml of heated wateris used to rinse the vessel out into the water phase to ensure completetransfer. The water phase is then heated and mixed at about 55±5° C.until the xanthan gum mixture is fully and evenly dispersed into theaqueous phase. The temperatures of both the water phase and oil phaseare both maintained at about 55±5° C. The aqueous phase is thentransferred into the oil phase and the speed of the Heidolph mixer isincreased during addition. The mixture is then homogenized on high speedfor about 3 min and transferred immediately back to the Heidolphmixture; however, the contents of the homogenized sample, about 2 L, aremixed at about room temperature and allowed to cool to about 35° C. Thecontainer and contents and the paddle from the overhead mixer are thenre-weighed and the weight of the paddle and 2 L beaker, as determinedabove, are subtracted to determine the total weight of the formulationremaining. The total weight (about 1 kg) of the cream is then made up toweight with heated water (Note: water evaporated during heating, whichneeds to be corrected at this point). The mixture is then transferredback onto the Heidolph mixer at about room temperature and mixed untilthe temperature of the formulation is below about 28° C. The lid of thecontainer is then placed onto the vessel and stored at room temperature.

The lower dosage strength formulations of this Example 23 are believedto be stable and consistent with the specifications for the commerciallyavailable Aldara® 5% imiquimod cream. More preferably, low dosageformulations of this Example 23, especially as to those lower dosagestrength formulations wherein the vehicle comprises an isostearic acidas the fatty acid, are believed to have the following:

(1) Stability. The imiquimod formulations of the present invention, whenthey are measured on HPLC at 25° C./60% RH, 30° C./65% RH and 40° C./75%RH over, one, two, three and six months, demonstrate stabilityconsistent with the Aid 5% imiquimod cream;

(2) Degradation Products. No degradation products are detected in theformulations of the present invention, at its current recommendedstorage temperatures of about 4-25° C. In addition, there are nodegradation products detected at any of the temperatures or time pointsmentioned under “Stability” above, when analyzed at about 318 nm.

(3) Homogeneity. The amount of imiquimod that is recovered from theformulations at any of the above-mentioned temperatures and time pointsis between about 90 to about 110% w/w thereby demonstrating goodhomogeneity;

(4) Benzyl Alcohol Content. The formulations of the present inventionare also within specifications for the Aldara® 5% imiquimod cream, i.e.,between 1.0% w/w and 2.1% w/w, at any of the above-mentionedtemperatures and time points as to benzyl alcohol content.

(5) Microscopic Stability. There is no change in the particle size andno crystals are detected in the formulations of the present inventionwhen they are stored at 25° C./60% RH and analyzed over a six monthperiod;

(6) Macroscopic Stability. There are no obvious physical changes in theformulations of the present invention when they are stored at 25° C./60%RH and analyzed over a six month period;

(7) Viscosity. The formulations of the present invention are within therange of the specifications for the Aldara® 5% imiquimod cream, i.e.,between 2000 cPs and 35,000 cPs, when they are stored at 25° C./60% RHand analyzed over a six month period; pH Stability. The formulations ofthe present invention are within the range of the specifications for theAldara® 5% imiquimod cream, i.e., between pH 4.0 and pH 5.5) when theyare stored at 25° C./60° % RH and analyzed over a six month period;

(8) Preservative Efficacy Test (“PET”). The formulations of the presentinvention demonstrate sufficient reductions in colony forming unitcounts for each of the organisms with which the formulations areinoculated, i.e., S. aureus, E. coli, Ps. Aeruginosa, C. albicans, andA. niger, at 2-8° C. and 40° C. over a 28 day test period and meet therequirements specified in both the USP and EP.

(9) Imiquimod In vitro Release. The Aldara® 5% imiquimod cream releasesstatistically significant (p<0.05) higher amounts of imiquimod over a 3hour time period in comparison to the lower dosage strength formulationsof the present invention through a synthetic membrane, e.g., Microporouspolyethylene film 3M No. 9711 CoTran™. There is no statisticaldifference (p<0.05) in the total cumulative amount of imiquimod that isreleased from any of the 3.75% w/w imiquimod formulations. There is nostatistical difference (p<0.05) in the total cumulative amount ofimiquimod that is released from any of the 2.5% w/w imiquimodformulations. The Aldara® 5% imiquimod cream also statisticallysignificantly (p<0.05) releases imiquimod at a faster rate over a 3 hourtime period in comparison to the lower dosage strength formulations ofthe present invention through a synthetic membrane, e.g., Microporouspolyethylene film 3M No. 9711 CoTran™. There is no statisticaldifference (p<0.05) between the imiquimod release rates for any of the3.75% w/w imiquimod formulations. There is no statistical difference(p<0.05) between the imiquimod release rates for any of the 2.5% w/wimiquimod formulations. Thus, the greater the amount of imiquimod in aformulation, the faster and greater the total amount of imiquimod thatis released from such formulation that the amount and rate of release ofimiquimod are concentration dependant and that the rates and amounts ofrelease of imiquimod from the formulations of the present invention arelinear and dose proportionate to the Aldara® 5% imiquimod cream;

(10) Imiquimod In vitro Skin Permeation (Franz Cell Study). With respectto statistical analyses, there is no statistical difference between thelower dosage strength formulations of the present invention and theAldara® 5% imiquimod cream as to the amount of imiquimod recovered fromthe receiver fluid, epidermis and dermis combined, Nonetheless, there isa statistically significant (p<0.05) dose proportionate differencebetween the amount of imiquimod recovered from each of the matrices withrespect to the concentration of imiquimod in the lower dosage strengthformulations of the present invention and the Aldara® 5% imiquimod creamfor both un-absorbed and stratum corneum. Thus there is a linear doserelease between the amount of imiquimod that is applied and recovered ineach of the matrices, i.e., receiver fluid, unabsorbed dose, stratumcorneum, epidermis and dermis.

ANOVA statistical analysis at 95% confidence level is used to analyzethe stability data generated, including the data generated for themembrane and skin permeation experiments.

It is also believed that the formulations of the present invention,including the formulations identified in this Example 23, haveHydrophilic-lipophilic balance (HLB) values between about 12 and 15, andmore preferably between about 12.4 and about 13.4.

I. Physical Characterization and Testing

The following is conducted for physical characterization of lower dosagestrength imiquimod formulations, e.g., formulations identified in Table12 and Table 18, and for testing lower dosage strength imiquimodformulations, e.g., imiquimod formulations identified in Tables 13-17.

(A) Analytical Method—HPLC Assay

A summary of an HPLC method is provided in Table 10.

TABLE 10 Summary of HPLC Methodology HPLC System HPLC 9. Waters 265(Alliance Separations module), Water 996 (Photodiode array detector),CPU (Compaq), Software-Microsoft Windows NT Version 4.00.1381 andAnalysis software-Millenium³² Version 4.00.00.00 Column SupelcosilLC-8-DB (5 mm, 15 × 0.46 cm) Guard Column Supelguard LC-8-DB 2 cmDetection UV at 258 nm Sample Temperature 25° C. Column Temperature 25°C. Flow Rate  2 ml/min Mobile Phase 72:28 aqueous:ACN (1% TEA solution,0.2% Octyl Sodium Sulfate, adjusted to pH 2.0 with H₃PO₄ InjectionVolume 20 μl Run Time 12 min Needle Wash 0:90 0.1N HCI:water

(B) Preparation of HPLC Reagents

Mobile Phase:

About 2.0 g octyl sodium sulfate (OSS) is weighed into a large beakerand is mixed with about 990 ml milli-Q ultrapure water and about 10.0 mlof triethylamine (TEA). The mixture is sonicated and stirred for about 5min to dissolve the solids. A pH meter is then placed in the mixture andthe pH of the OSS/TEA solution is adjusted to about 2.0 withconcentrated H₃PO₄, stirring continuously during the adjustingprocedure. The entire mixture is then filtered through a 0.2 μm filter.The filtrate is mixed with acetonitrile (HPLC grade) in the ratio ofabout 72:28 aqueous:acetonitrile by volume.

Sample Diluent

About 250 ml acetonitrile (HPLC grade), about 740 ml purified water andabout 10 ml of concentrated HCl are mixed together in a 1 L volumetricflask.

Receiver Fluid

About 100 ml of a commercially available standardized 1N HCl solution isdiluted to about 1000 ml with Milli-Q ultra pure water.

Standards

Imiquimod standards are prepared, as described under Sample Diluent andReceiver Fluid, for stability test and receiver for membrane releasetests. Initially, a stock solution of imiquimod is prepared bydissolving about 25 mg of imiquimod into about 50 ml of solvent (eitherSample Diluent or Receiver Fluid) to give a concentration of about 500μg/ml in Sample Diluent or Receiver Fluid.

A calibration range as shown in Table 11 is prepared for each HPLC run.

TABLE 11 Preparation of Calibration Standards Volume of stock Finalconcentration solution Volume of Test (ml) of diluent Item (gg,/m1) 10 0500 5 5 250 4 6 200 2 8 100 1 9 50 0.5 9.5 25 0.2 9.8 10 0.1 9.9 5

Combination Standard

The following combination standard solution is also prepared; whereby,about 500 mg of methylparaben and about 50 mg propylparaben are weighedinto a single 250 ml volumetric flask and is diluted to volume withsample diluent above, to form the parabens solution. In addition, about500 mg of imiquimod and about 200 mg benzyl alcohol are also weighedinto a single 100 ml volumetric flask and about 10 ml of the parabenssolution is then transferred into the imiquimod/benzyl alcoholvolumetric which is made up to volume with diluent and is sonicated todissolve fully.

Impurity Standards

Impurity standards are prepared separately at a concentration of about50 p·g/ml in Sample Diluent and are analyzed in each HPLC run. Theimpurity standards that are included in each HPLC run are as follows:

-   -   N-propyl imiquimod    -   N-methyl imiquimod    -   4-hydroxyimiquimod    -   4-chloro imiquimod

TABLE 12 2.5% Imiquimod Formulations 3.75% Imiquimod Formulations 235236 237 238 239 240 241 242 243 244 181 245 % w/w % w/w % w/w % w/w %w/w % w/w % w/w % w/w % w/w % w/w % w/w % w/w Excipients Isostearic acid15 10 15 10 15 15 15 20 15 20 15 20 Cetyl alcohol 2 4 4 2 2 4 2 2 2 2 44 Stearyl alcohol 2 2 2 2.4 2.4 2.4 2 2 2.4 2.4 2.4 2.4 White petrolatum3.4 3.4 2.8 2.8 3.4 2.8 3.4 2.8 3.4 2.8 2.8 3.4 Polysorbate 60 3.8 3.8 33.8 3 3.8 3 3.8 3 3 3 3.8 Sorbitan 0.2 1 1 1 1 0.2 1 1 0.2 0.2 1 1Monostearate Glycerine 3 1 3 3 1 1 3 1 1 3 1 3 Xanthan gum 0.3 0.3 0.70.3 0.7 0.3 0.3 0.7 0.7 0.3 0.3 0.7 Purified water 65.58 69.78 63.7869.98 66.78 65.78 64.33 60.73 66.33 60.33 64.53 55.73 Benzyl alcohol 2 22 2 2 2 2 2 2 2 2 2 Methylparaben 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.20.2 0.2 0.2 Propylparaben 0.02 0.02 0.02 0.02 0.02 0.02 0.02 0.02 0.020.02 0.02 0.02 Imiquimod 2.50 2.50 2.50 2.50 2.50 2.50 3.75 3.75 3.753.75 3.75 3.75 Total amount (g) 100.00 100.00 100.00 100.00 100.00100.00 100.00 100.00 100.00 100.00 100.00 100.00 HLB Values 14.4 12.812.4 12.8 12.4 14.4 12.4 12.8 14.3 14.3 12.4 12.8

In Table 13, fifteen 2.5% w/w imiquimod formulations are manufactured in100 g batches. Each of the fifteen formulations are assessed formacroscopic and microscopic appearance, as discussed hereinafter.

TABLE 13 246 110 116 247 117 248 249 250 Imiquimod % % % % % % % %Formulation w/w w/w w/w w/w w/w w/w w/w w/w Excipients Isostearic acid15.00 15.00 15.00 10.00 15.00 15.00 10.00 25.00 Cetyl alcohol 2.20 2.202.20 2.20 2.20 2.20 2.20 2.20 Stearyl alcohol 3.10 3.10 3.10 3.10 3.103.10 3.10 3.10 White petrolatum 15.50 3.00 6.00 8.50 6.00 6.00 8.50 3.00Polysorbate 60 3.40 3.40 3.40 3.40 3.00 4.25 3.00 3.40 SorbitanMonostearate 0.60 0.60 0.60 0.60 1.00 0.75 1.00 0.60 Glycerine 2.00 2.005.00 5.00 5.00 5.00 5.00 2.00 Xanthan gum 0.50 0.50 0.50 0.50 0.50 0.500.50 0.50 Purified water 52.98 65.48 59.48 61.98 59.48 58.48 61.58 55.48Benzyl alcohol 2.00 2.00 2.00 2.00 2.00 2.00 2.00 2.00 Methylparaben0.20 0.20 0.20 0.20 0.20 0.20 0.20 0.20 Propylparaben 0.02 0.02 0.020.02 0.02 0.02 0.02 0.02 Imiquimod 2.50 2.50 2.50 2.50 2.50 2.50 2.502.50 Total amount (g) 100.00 100.00 100.00 100.00 100.00 100.00 100.00100.00 HLB Values 13.4 13.4 13.4 13.4 12.4 13.4 12.4 13.4 113 251 252253 254 120 121 Imiquimod % % % % % % % Formulation w/w w/w w/w w/w w/ww/w w/w Excipients Isostearic acid 15.00 15.00 10.00 12.5 12.5 25.0025.00 Cetyl alcohol 2.20 2.20 2.20 2.20 2.20 2.70 2.20 Stearyl alcohol3.10 3.10 3.10 3.10 3.10 3.80 3.10 White petrolatum 6.00 6.00 5.00 5.005.00 3.00 3.00 Polysorbate 60 3.00 3.00 3.40 3.40 3.00 3.40 3.40Sorbitan Monostearate 1.00 1.00 0.60 0.60 1.00 0.60 0.60 Glycerine 5.005.00 5.00 5.00 5.00 2.00 2.00 Xanthan gum 0.75 1.00 0.50 0.50 0.50 0.501.00 Purified water 59.23 58.98 60.48 62.98 62.98 54.28 54.98 Benzylalcohol 2.00 2.00 2.00 2.00 2.00 2.00 2.00 Methylparaben 0.20 0.20 0.200.20 0.20 0.20 0.20 Propylparaben 0.02 0.02 0.02 0.02 0.02 0.02 0.02Imiquimod 2.50 2.50 2.50 2.50 2.50 2.50 2.50 Total amount (g) 100.00100.00 100.00 100.00 100.00 100.00 100.00 HLB Values 12.4 12.4 13.4 13.412.4 13.4 13.4

TABLE 14 2.5% Imiquimod 110 116 117 250 254 120 121 235 123 124 125 126Formulations % w/w % w/w % w/w % w/w % w/w % w/w % w/w % w/w % w/w % w/w% w/w % w/w Excipients Isostearic acid 15.00 15.00 15.00 25.00 12.525.00 25.00 15 20.00 20.00 20.00 20.00 Cetyl alcohol 2.20 2.20 2.20 2.202.20 2.70 2.2 2 2.20 2.20 2.20 2.20 Stearyl alcohol 3.10 3.10 3.10 3.103.10 3.80 3.10 2 3.10 3.10 3.10 3.10 White petrolatum 3.00 6.00 6.003.00 5.00 3.00 3.00 3.4 5.00 3.00 5.00 3.00 Polysorbate 60 3.40 3.403.00 3.40 3.00 3.40 3.40 3.8 3.40 3.40 3.40 3.40 Sorbitan 0.60 0.60 1.000.60 1.00 0.60 0.60 0.2 0.60 0.60 0.60 0.60 Monostearate Glycerine 2.005.00 5.00 2.00 5.00 2.00 2.00 3 2.00 5.00 5.00 2.00 Xanthan gum 0.500.50 0.50 0.50 0.50 0.50 1.00 0.3 0.50 0.50 0.50 0.50 Purified water65.48 59.48 59.48 55.48 62.98 54.28 54.98 65.58 58.48 57.48 55.48 60.48Benzyl alcohol 2.00 2.00 2.00 2.00 2.00 2.00 2.00 2 2.00 2.00 2.00 2.00Methylparaben 0.20 0.20 0.20 0.20 0.20 0.20 0.20 0.2 0.20 0.20 0.20 0.20Propylparaben 0.02 0.02 0.02 0.02 0.02 0.02 0.02 0.02 0.02 0.02 0.020.02 Imiquimod 2.50 2.50 2.50 2.50 2.50 2.50 2.50 2.50 2.50 2.50 2.502.50 Total 100.00 100.00 100.00 100.00 100.00 100.00 100.00 100.00100.00 100.00 100.00 100.00 HLB Values 13.4 13.4 12.4 13.4 12.4 13.413.4 14.4 13.4 13.4 13.4 13.4

TABLE 15 3.75% Imiquimod 182 188 189 183 184 255 193 245 195 256 197Formulations % w/w % w/w % w/w % w/w % w/w % w/w % w/w % w/w % w/w % w/w% w/w Excipients Isostearic acid 20.00 20.00 20.00 25.00 18.75 25.0025.00 20 20.00 20.00 20.00 Cetyl alcohol 2.20 2.20 2.20 2.20 2.20 2.702.20 4 2.20 2.20 2.20 Stearyl alcohol 3.10 3.10 3.10 3.10 3.10 3.80 3.102.4 3.10 3.10 3.10 White 3.00 6.00 6.00 3.00 5.00 3.00 3.00 3.4 5.003.00 5.00 petrolatum Polysorbate 60 3.40 3.40 3.00 3.40 3.00 3.40 3.403.8 3.40 3.40 3.40 Sorbitan 0.60 0.60 1.00 0.60 1.00 0.60 0.60 1 0.600.60 0.60 Monostearate Glycerine 2.00 5.00 5.00 2.00 5.00 2.00 2.00 32.00 5.00 5.00 Xanthan gum 0.50 0.50 0.50 0.50 0.50 1.00 1.00 0.7 0.500.50 0.50 Purified water 59.23 53.23 53.23 54.23 55.48 53.73 53.73 55.7357.23 58.23 54.23 Benzyl alcohol 2.00 2.00 2.00 2.00 2.00 2.00 2.00 22.00 2.00 2.00 Methylparaben 0.20 0.20 0.20 0.20 0.20 0.20 0.20 0.2 0.200.20 0.20 Propylparaben 0.02 0.02 0.02 0.02 0.02 0.02 0.02 0.02 0.020.02 0.02 Imiquimod 3.75 3.75 3.75 3.75 3.75 3.75 3.75 3.75 3.75 3.753.75 Total 100.00 100.00 100.00 100.00 100.00 100.00 100.00 100.00100.00 100.00 100.00 HLB Values 13.4 13.4 12.4 13.4 12.4 13.4 13.4 12.813.4 13.4 13.4

In Table 16, compositions for Aldara® 5% imiquimod cream and 1%imiquimod cream formulations are shown. Also shown in the Table 16, arefour placebo formulations Pbo1, Pbo2, Pbo3 and formulation Pbo4,

TABLE 16 3M Aldara ® (5% 257 Placebos Bulk) (1%) Pbo1 Pbo2 Pbo3 Pbo4Formulations % w/w % w/w % w/w % w/w % w/w % w/w Excipients Isostearicacid 25.00 25.00 20.00 20.00 20.00 20.00 Cetyl alcohol 2.20 2.40 2.202.20 2.20 2.20 Stearyl alcohol 3.10 3.40 3.10 3.10 3.10 3.10 Whitepetrolatum 3.00 3.00 5.00 3.00 5.00 3.00 Polysorbate 60 3.40 3.40 3.403.40 3.40 3.40 Sorbitan 0.60 0.60 0.60 0.60 0.60 0.60 MonostearateGlycerine 2.00 2.00 2.00 5.00 5.00 2.00 Xanthan gum 0.50 0.50 0.60 0.600.50 0.50 Purified water 52.98 58.48 80.98 59.98 57.98 62.98 Benzylalcohol 2.00 2.00 2.00 2.00 2.00 2.00 Methylparaben 0.20 0.20 0.20 0.200.20 0.20 Propylparaben 0.02 0.02 0.02 0.02 0.02 0.02 Imiquimod 5.001.00 0.00 0.00 0.00 0.00 Total 100.00 100.00 100.00 100.00 100.00 100.00HLB Values 13.37 13.37 13.37 13.37 13.37 13.37

(C) Uniformity/Homogeneity

Following a 1 kg batch manufacturing process as described in thisExample 23, 3×150 mg samples (top, middle and bottom) are removed fromeach 1 kg bulk batch using a positive displacement pipette and areextracted and are analyzed as described in Section, entitled “imiquimodContent” described hereinafter.

(D) Preparation of Stability Samples

Each of the 1 kg batches are sub-aliquoted individually into 21×60 mlglass powder jars, where:

(B) 5 × 50 g (25° C./60% RH t = 0 h, 1 month, 2 months, 3 months, 6months) (C) 5 × 50 g (30° C./65% RH − t = 0 h, 1 month, 2 months, 3months, 6 months) (D) 5 × 50 g (40° C./75% RH − t = 0 h, 1 month, 2months, 3 months, 6 months) (E) 1 × 60 g (PET sample, placed at 2-8° C.)(F) 1 × 20 g (placed at 2-8° C.) (G) 1 × 20 g (placed at −20° C.) (H)The remaining formulation, is divided into 3 additional aliquots andeach is placed at 25° C./60% RH, 30° C./65% RH and 40° C./75% RH.

All batches are characterised based on the protocols that are shown inSection entitled Protocol for the Assessment of Formulations. Once eachaliquot is removed from the relevant stability conditions at each timepoint; the remaining aliquot from each sample is placed in a fridge at2-8° C. for future reference if required.

Following the 1 month stability time point, the benzyl alcohol contentof the formulations are monitored; for all subsequent time points, theplacebo formulations are analyzed by HPLC. Thus, there are no t=0measurements for benzyl alcohol content for placebo formulations Pbo1,Pbo2 and Pbo3.

(E) Protocol for the Assessment of Formulations

The protocols that are used for the assessment of the formulations areas follows:

(1) Macroscopic Appearance

Macroscopic appearance is determined by visual examination of thephysical characteristics which include appearance and texture of eachcream. Macroscopic appearance is performed at each time point (t=0, 1,2, 3 and 6 months) for the 25° C. stability samples, as follows:

-   -   (A) Using a medium Granton® pallet knife, a small aliquot of        sample (approximately 1 to 2 g) is removed from its container        and is placed on the surface of a large Granton® pallet knife.    -   (B) The medium Granton® pallet knife is then used to smooth the        cream over the surface of the large Granton® pallet knife, by        using a backward and forward motion of the spatula until a        visually uniform layer of cream is obtained on the large        Granton® pallet knife.    -   (C) Visual observations of the cream are recorded which are        based on, the presence of lumps, graduals or ease of spread over        the surface of the spatula.

(2) Microscopic Appearance

Formulations are viewed under a light microscope (Leica DME FD198536Light Microscope), to determine particle size, uniformity and theabsence of particulates. Digital images of each formulation are taken ateach time point (t=0, 1, 2, 3 and 6 months) for the 25° C. stabilitysamples, as follows:

-   -   (A) The microscope is set up so that the camera (Nikkon Cool Pix        4500 digital camera) is attached to the relay lens of the        microscope and the 40× objective lens is set into place to view        the sample. Camera settings: Image size: 1280×960 pixels, Image        quality: Fine.    -   (B) A small droplet of the formulation to be viewed is placed        onto a microscope slide (Fisher-brand microscope slides, Cat        No. 7101) using a micro-spatula. The microscope slide is then        covered using a cover glass (Fisher-brand cover glass, width:        22-32 mm, thickness: 0.13-0.17 mm).    -   (C) The microscope slide with the formulation is then placed        under the 40× objective. Using the fine adjustment knob of the        light microscope, the slide is brought into sharper focus to get        a clear view.    -   (D) Once a clear distinct view is obtained, pictures are taken        (×400 magnification).    -   (E) The particle sizes of formulations prepared are determined        using a graticule (Olympus, Objective Micrometer, 0.01 mm).        Overall uniformity and particle size are measured using the        scale on a calibrated graticule. Five random locations on each        slide for each formulation are chosen to assess uniformity and        particle size.

(3) Imiquimod Content

The imiquimod content of the formulations is measured at each time point(t=0, 1, 2, 3 and 6 months) for the 25° C. and 40° C. stability samples.The 30° C. stability samples are removed from the stability cabinet ateach time point and placed at about 2-8° C. for future reference, asfollows:

-   -   (2) About 150 mg of the formulation is removed from each sample        and is transferred into a 50 ml volumetric flask.    -   (3) About 30-40 ml of diluent (about 250 ml acetonitrile (HPLC        grade), about 740 ml purified water and about 10 ml of        concentrated HCl are mixed together in a 1 L volumetric flask)        is then added to the volumetric flask containing the aliquot of        the formulation.    -   (4) The sample is then vortex mixed for approximately 1 min or        until the formulation has visibly completely dispersed into the        diluent.    -   (5) The sample is then sonicated for about 5 min and then is        left to cool to room temperature.    -   (6) The sample is then filled to volume with diluent and is        mixed by inverting the volumetric flask.    -   (7) This step is followed by filtration through a 0.45 mm filter        directly into a 2 ml HPLC vial and the cap crimped.    -   (8) The sample is then analysed on the HPLC using the method        described in Section entitled Analytical Method—HPLC Assay        described above, with the standard solutions as described above        in Sections entitled Standards Combination Standard and Impurity        Standard. This method also allows for the detection and        measurement of benzyl alcohol.

(4) Related Substances/Degradation Products

Following the extraction and analysis, as described above underImiquimod Content, the chromatograms for each formulation are comparedto those generated for the impurity standards, as described above underImpurity Standards, to identify if there are any degradation peakspresent. As the preservatives have similar retention times as thedegradation products, the chromatograms are viewed at an absorbance of318 nm wavelength at which the preservatives do not absorb to confirmthe absence of degradation products.

(5) pH Measurements

The pH of the formulations are measured at each time point (t=0, 1, 2, 3and 6 months), The pH measurement protocol is as follows:

-   -   (4) A small sample of the formulation is applied on to the        surface of a strip of pH paper (Fisher-brand pH paper: FB33045,        Range pH 0.5-5.5) and is spread evenly over the surface using a        spatula.    -   (5) The pH paper with the formulation on it is then left for 10        min to ensure that the paper does absorb the cream (which is        confirmed by a color change).    -   (6) The pH of the formulation is then determined by comparing        the color on the strip of pH paper with a range of colors (color        chart) that are provided with the Fisher-brand pH paper.

(6) Viscosity from Flow Curve (Rheology Bohlin CVO Measurements)

The rheology of the formulations are measured at each time point (t=0,1; 2, 3 and 6 months) for the 25° C. stability samples.

(7) Rheology Oscillation Methodology (Bohlin CVO)

The Crossover and G^(I) values of the ICH stability samples are measuredfor all the t=0 samples. See e.g., Tables 18 and 26. The ‘crossover’point is an indication of the elastic structure of the formulation and ahigh cross over point indicates that more force is required to breakdownthe formulation thus providing an indication for longer term stabilityof the cream formulations. The G^(I) value is a measurement of theelastic part of the formulation, whereby a high G^(I) value indicates amore rigid formulation which ‘recovers’ more easily from applied shearstress.

(8) Viscosity (Brookfield) Measurements

The viscosity of the formulations is measured at each time point (t=0,1, 2, 3 and 6 months) for the 25° C. stability samples.

(9) Preservative Efficacy Test Protocol

The preservative efficacy test is performed on formulations 110, 126,Pbo4 and 182 which are stored at about 2-8° C. and about 40° C. forabout 3 months. Preservative efficacy testing is carried out accordingto the procedure described in line with the methodology described in theUSP 2007 and EP 2007. The time points, at which the inoculated samplesare tested are: 0 h, 24 h, 48 h, 7 days, 14 days, 21 days and 28 days.

Method validation is performed using Staphylococcus aureus cultures toconfirm the neutralizing effect of DIE broth, for this purpose 110 and182 are used to confirm neutralization of the preservatives.

II. Test Item Release Studies Through Synthetic Membranes

(A) In Vitro Screening of Release Profiles Through Synthetic Membranes

The release of imiquimod from 13 formulations (n=4 for each) arecompared using methodology based on the principles of the FDA, SUPAC-SSguidelines. The formulations that are tested included: 3M's Aldara® 5%imiquimod cream 1 kg bulk sample, Aldara® 5% imiquimod cream sachet(commercial product), Graceway's Aldara® 5% imiquimod cream 1 kg batch,and formulations 257 (1%), 123, 250, 125, 110, 182, 195, 256, 197 and183. The protocol for the investigation is as follows:

A synthetic membrane (Microporous polyethylene film 3M No. 9711 CoTran™)is mounted in a small Franz cell (refer to FIG. 1) with a receiver fluid(0.1 N HCl) to ensure sink conditions (is equilibrated for a minimum of30 min prior to dosing). An infinite dose of formulation (230 to 250 μlis dispensed using a calibrated positive displacement pipette) isapplied to the membrane (using the pipette tip to gently spread over thesurface) and the diffusion of imiquimod that is measured over time (n=4per formulation). Briefly 200 μl of the receiver fluid is removed usinga 250 μl Hamilton syringe at each time point (0, 15, 30, 60, 120 and 240min) and is analysed on the HPLC using the method, as described underAnalytical Method—HPLC Assay. The sample of receiver fluid is removed ateach time point and is replaced with fresh pre-warmed (32° C.) receiverfluid.

III. In Vitro Skin Permeation Study

(A) Analytical Methods

(1) Liquid Scintillation Method Details

Samples are added to a scintillation vial and about 4 ml ofscintillation cocktail (Hionic-fluor) is added. The vial is capped andis shaken using a vortex mixer until the sample is mixed with thescintillation cocktail. The scintillation vials are then loaded intoracks before analysing on the scintillation counter, using the settingslisted as follows.

Model of scintillation counter: Beckman LS 5000 CE

Isotope setting: C₁₄

Counting time: 5 min

Calculation mode: SL DPM

Count samples: 1 times

Replicates: 1

Quench monitor: Yes

(B) Radioactive Purity of Imiquimod¹⁴C

(1) Preparation of Stock

The radio-labelled material is as follows:

Imiquimod stock (^(C)14): Specific activity of about 57 mCl/mmol with aradiochemical purity of about 99.2% is supplied as a powder in aborosilicate multi-dose vial with additional screw cap.

Working stock solutions are prepared by addition of 1 ml isostearic acidto the imiquimod powder using a needle and syringe inserted through theseptum of the vial. The screw cap is then replaced securely and the vialshaken on a vortex mixer until all the imiquimod dissolves in theisostearic acid. The homogeneity is also confirmed. This results in astock solution containing about 1000 Ci/ml.

(C) Preparation of Formulations

The method for the preparation of about a 100 g radioactive batch is asfollows:

-   -   The glass container and mixer paddle attachment are placed onto        a balance and the weight is recorded before the container and        paddle are removed.    -   The amount of imiquimod required for the formulation is added by        weight and the remaining isostearic acid (minus 1.38 g) and        benzyl alcohol are added to the container.    -   The entire mixture is heated in a water bath at about 55±5° C.        while stirring with a small over head mixer (IKA®-Werke Lab Egg)        and paddle attachment.    -   Cetyl alcohol, stearyl alcohol, white petrolatum, polysorbate 60        and sorbitan monostearate are added into the beaker and mixed at        about 55±5° C. until the oil phase is completely in solution.    -   Separately, about 200 ml of water is heated in a beaker to about        55±5° C. while stirring with a magnetic follower.    -   About 50 ml of the heated water is transferred into a beaker and        is placed in a water bath maintained at about 55±5° C. and half        the glycerine, methyl hydroxyparabens and propyl hydroxyparabens        are added (where both methyl and propyl parabens are weighed        into weighing boats first) to the water and is stirred at about        55±5° C. (this is the aqueous phase).    -   The remaining glycerine is added to a 28 mi vial with the        xanthan gum and is mixed using a small over head mixer        (IKA®-Werke Lab Egg) with paddle attachment for about 10 min.    -   The glycerine and xanthan mixture are then added into the vortex        of the aqueous phase, using about a 5 ml aliquot of heated water        to rinse the vessel out into the water phase.    -   Mixing of the water phase is continued for at least about 5 min.    -   The aqueous phase is transferred into the oil phase, increasing        the stirring speed during addition.    -   The mixture is stirred on high speed maintaining the temperature        at about 55±5° C. for 30 min.    -   The vessel is removed from the mixer and is homogenised using        the 1 cm head for about 3 min.    -   Mixing is continued while cooling to about 35° C. and the total        weight of the cream is made up to weight with heated water. The        mixture is transferred to the overhead stirrer and cooling and        stirring is continued to about 25° C.    -   The formulations are then aliquoted in to screw top vials and        are sealed with Parafilm® placed around the screw top lid.    -   About 9.862 g of the formulation is weighed into a vial and is        placed in a water bath at about 5° C. About 138 mg of        radio-labelled working stock solution is then added to the        formulation and the formulation is thoroughly mixed using a        spatula while cooling.

(D) Homogeneity Control

Following manufacturing of the formulations, the following test isperformed:

For each of the formulations, three aliquots (top, middle and bottom ofbatch) of approximately 5 mg is exactly weighed directly into ascintillation vial, where about 4 ml of scintillation cocktail is added.All of the samples are then directly quantified on the LiquidScintillation Counter (“LSC”) to confirm homogeneity within ±10%.

(E) Franz Cell Study

The method involves the use of full thickness human skin that is mountedin a Franz cell with about a 0.01 N hydrochloric acid as receiver fluidto ensure sink conditions. A dose of formulation equivalent to about 10mg/cm² is applied to the membrane and the diffusion of imiquimod ismeasured over time. Human skin from cosmetic reduction surgery is used.Subcutaneous fat is removed mechanically prior to preparation of theskin section for the study. The formulations (6μ) are applied to thesurface of the membrane using a positive displacement pipette. Theinvestigation is performed in several experiments. Two skin donors areused randomly and are assigned across all experiments so that eachformulation is tested on both skin donors. Each experiment consists oftwo randomly assigned formulations (n=6 cells per formulation) and twocomparator formulations (n=6 cells per comparator). The receptorcompartment of the Franz cells is then filled with the receiver fluidand the cells are fixed in a water bath maintained at about 37° C. Thereceptor compartment contents are continuously agitated by smallmagnetic followers. At t=1, 8 and 24 h, samples of receiver fluid aretaken from the receptor compartment, and are replaced with freshreceiver fluid and are assayed by scintillation counting.

(F) Mass Balance

At the end of the experiment, a mass balance experiment is carried out,where the amount of ¹⁴Cimiquimod remaining in the donor compartment,surface residue, Stratum corneum (SC), remaining epidermis, dermis andreceiver compartment is quantified. This method involves removal of theSC by tape stripping and processing of the remaining epidermal layer anddermis using standard procedures. The protocol for the mass balance isas follows:

Unabsorbed dose: The surface of each Franz cell donor chamber is wipedgently with a cotton bud using 5 clockwise and anti-clockwise movements.This procedure is repeated on 4 occasions using alternate wet (receiverfluid) and dry cotton buds. The cotton buds are added to scintillationcocktail before analysis. Two tape strips are removed from the skin andthese are regarded as unabsorbed formulation and included in the totalsurface activity. The Stratum corneum (SC) is removed by carefully tapestripping the membrane ten times using Scotch adhesive tape.Collectively, each tape is placed into a scintillation vial to which 4ml of scintillation cocktail are added before analysis. Epidermal layer:The remaining section of the epidermis (following tape stripping) iscarefully removed from the dermis with a scalpel. The epidermis isplaced into a glass vial containing 2 ml of Soluene 350 and is incubatedat about 50° C. for about 72 h before analysis by LSC. The remainingdermal layer is placed in to a glass vial containing about 2 ml ofSoluene 350 and is incubated at about 50° C. for about 72 h beforeanalysis by LSC.

(G) Analysis of Data

ANOVA statistical analysis at a 95% confidence level is used to analysethe data generated for the membrane release and skin permeationexperiments.

An example of the ANOVA statistical analysis is as follows:

Individual 05% CIs For Mean Base on Pooled StDev Level N Mean StDev+------------ +------------ +------------ +------------ Formulation X 44605.5 626.9 (---*---) Formulation Y 4 1862.8 185.9 (---*---)Formulation Z 4 1845.6 206.4 (---*---) +------------ +------------+------------ +------------ 0 1500 3000 4500

Whereby, no significance (p>0.05) is shown by two overlapping histograms(e.g. Y and Z), whereas a significant difference (P≤0.05) can beidentified by two histograms which don't overlap (e.g. X and Y and X andZ). The width of the each histogram is a reflection of the pooledstandard deviation from all data sets.

IV Results and Discussion

(A) Degradation Product Analysis

It is discovered that the preservatives (benzyl alcohol, methylparabenand propylparaben) at about 318 in the imiquimod formulations can not bedetected. Thus, by analysing the imiquimod formulations at thiswavelength, it permits the detection of degradation products, if any, inthe presence of preservatives. However, no degradation products areidentified at about 318 nm for any of the imiquimod formulations testedup to and including the 6 month stability time point at about 25° C. andabout 40° C.

In Table 17 and FIG. 2, they show a summary of the findings, wherebysimple microscopic analysis of the imiquimod formulations identifyformulations with inconsistent particle size and large aggregation ofmaterial. Summary and composition of lower dosage strength imiquimodformulations are listed in Table 13 and Table 14.

TABLE 17 246 110 116 247 117 248 249 250 113 251 252 253 254 120 121 % %% % % % % % % % % % % % % w/w w/w w/w w/w w/w w/w w/w w/w w/w w/w w/ww/w w/w w/w w/w Vis- high High high high high high high low high highhigh Med high very med- cosity ium- high ium (visual) high low Appear-lumpy Smooth smooth smooth smooth smooth smooth smooth slight- Tex-smooth Smooth matt, matt, smooth ance ly tured smooth smooth (spa- tex-tula) tured pH 5 5 5 5 4.5 4.5 5 4 5 5 5 5 5 4.5 4.5 G¹ (Pa) 3639 1150.51504 1093 1740.5 5235 1364.5 171.5 642 943 626.5 567 2285.5 5231 304.5Cross- 29.5 14.5 20.5 16 21.5 none 21.5 13 21.5 29.25 19 15 21.5 20.529.75 over (o¹) Micro- v. bad Ok good bad good v.bad bad good bad bad okBad ok ok good scope

TABLE 18 Physical Characteristics of 12 Lower Dosage Strength ImiquimodFormulations, i.e., Formulations 181, 235, 236, 237, 238, 239, 240, 241,242, 243, 244 and 245, 235 236 237 238 239 240 241 242 243 244 181 245 %w/w % w/w % w/w % w/w % w/w % w/w % w/w % w/w % w/w % w/w % w/w % w/wExcipients Isostearic acid 15 10 15 10 15 15 15 20 15 20 15 20 Cetylalcohol 2 4 4 2 2 4 2 2 2 2 4 4 Stearyl alcohol 2 2 2 2.4 2.4 2.4 2 22.4 2.4 2.4 2.4 White 3.4 3.4 2.8 2.8 3.4 2.8 3.4 2.8 3.4 2.8 2.8 3.4petrolatum Polysorbate 60 3.8 3.8 3 38 3 3.8 3 3.8 3 3 3 3.8 Sorbitin0.2 1 1 1 1 0.2 1 1 0.2 0.2 1 1 Monostearate Glycerin 3 1 3 3 1 1 3 1 13 1 3 Xanthan gum 0.3 0.3 0.7 0.3 0.7 0.3 0.3 0.7 0.7 0.3 0.3 0.7Purified water 66.58 69.79 63.78 69.98 66.78 65.78 64.33 60.73 66.3360.33 86.53 55.73 Benzyl alcohol 2 2 2 2 2 2 2 2 2 2 2 2 Methylparaben0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2 Propylparaben 0.02 0.020.02 0.02 0.02 0.02 0.02 0.02 0.02 0.02 0.02 0.02 Imiquimod 2.50 2.502.50 2.50 2.50 2.50 3.75 3.75 3.75 3.75 3.75 3.75 Total 100.00 100.00100.00 100.00 100.00 100.00 100.00 100.00 100.00 100.00 100.00 100.00amount (g) HLB Values 14.39 12.78 12.35 12.79 12.35 14.39 12.35 12.7814.26 14.26 12.35 12.78 Modification multi multi multi multi multi multimulti multi multi multi multi multi Viscosity low/med high high mediummed/high high Medium- Medium Medium- Medium- Very High High Low highHigh pH 4.7 4.7 4.7 6 4.7 4.7 5.0 4.7 4.7 4.5 4.7 4.5 G 294.37 1527.65639.345 467.78 552.61 924.075 116.18 416.65 8767 65.425 2514.25 1280.05crossover 9.5 25.25 10.5 17.75 12 25.5 13.75 18.5 none 11.75 36 22.5microscope v.good ok, but bad good, but bad bad- good with very ok goodvery good particles? particles? particles? bubbles good good Appearance/glossy, smooth slight glossy, v. glossy & smooth, glossy, glossy,glossy, glossy, smooth glossy, Spatula v slight matt, texture, smooth v.smooth matt slightly textured slightly very with a smooth, texture,slightly matt, textured with textured, slightly matt with matt, aerateddoes with some very textured appear- some does smooth some aerationaerated ance aeration smooth out aeration out

(B) Scale-Up and ICH Stability

(1) Homogeneity

In Table 19, formulations 245, 121 and 193 show signs of phaseseparation. All the other formulations in Table 19 show goodhomogeneity, and are subsequently sub-aliquoted and placed on stabilityas described above under Preparation of Stability Samples.

TABLE 19 Homogeneity Results from 1 kg batches, where Samples areRemoved from Top Middle and the Bottom of the Batch for Comparison ofHomogeneity. Formulation % Recovery % CV 3M Aldara ® 5% Batch 102.69 ±2.29 2.23 257 (1%) 100.29 ± 0.68 0.68 197  96.81 ± 2.15 2.22  83  97.56± 0.48 0.50 245  91.08 ± 12.80 14.06 182  97.68 ± 0.73 0.75 189  98.32 ±0.92 0.94 184  98.37 ± 1.61 1.63 193  97.21 ± 0.22 0.23 188  98.95 ±2.48 2.51 195  99.66 ± 0.70 0.70 255  99.46 ± 0.49 0.49 256  98.80 ±0.75 0.76 Graceway Aldara ® 5% 102.74 ± 1.26 1.23 Imiquimod 110 101.43 ±0.63 0.62 116 100.39 ± 0.18 0.18 117 100.49 ± 0.64 0.64 250  99.98 ±0.37 0.37 254  98.70 ± 0.21 0.21 120 100.02 ± 0.34 0.34 121 106.22 ±0.09 0.09 235 101.04 ± 0.21 0.21 123 101.75 ± 0.28 0.28 124  95.00 ±0.32 0.34 125 101.12 ± 0.12 0.12 126 102.37 ± 0.58 0.57 Pbo1 N/A N/APbo2 N/A N/A Pbo3 N/A N/A Pbo4 N/A N/A

(C) Stability

(1) Stability of Imiquimod in Formulations

In Table 20, imiquimod in the formulations is stable at both about 25°C. and about 40° C. over an about six month period, although the resultsfor three and six months at both about 25° C. and about 40° C. lookconsistently higher than previous time points. This could be attributedto a small amount of water evaporation from the containers. In addition,all samples are consistent with the commercially supplied Aldara® 5%imiquimod cream sample. There are no degradation products detected inany of the samples in Table 20 at any of the temperatures and timepoints when analyzed at about 318 nm With reference to formulationspecification, the specification amount of imiquimod that is recoveredfrom the samples in Table 20 is between about 90%-110% w/w, therebyconfirming that the samples fall within their target specification. Inother words, and by way of example, the specification amount ofimiquimod that is recovered from preferred 2.5% imiquimod formulationsof the present invention will fall within between about 2.25% and about2.75% w/w and the amount of imiquimod that is recovered from preferred3.7.5% imiquimod formulations of the present invention will fall withinbetween about 3.38% and about 4.12% w/w, Thus, in accordance with thepresent invention, the amount of imiquimod recovery from preferredformulations will fall within about the 100%±10% w/w specification oftheir target concentrations.

TABLE 20 Percentage of Imiquimod that is Recovered from the Formulationsas Compared to Theoretical when the Formulations are Stored at 25° C.and 40° C. over a 6 Month Period. Highlighted Grey Areas Indicate TimePoints Which Are Not Tested Due To Rejection/Omission Of Formulations (n= 3 ± sd). Imiquimod T-0 T-1 month 25° C. T-1 month 4° C. T-2 months 25°C. T-2 months 40° C. T-3 months 25° C. T-3 months 40° C. T-6 months 25°C. T-6 months 40° C. Formulations Mean SD Mean SD Mean SD Mean SD MeanSD Mean SD Mean SD Mean SD Mean SD Aldara ® 100.38 ± 0.25 100.60 ± 0.10100.41 ± 0.04 100.58 ± 0.10 101.40 ± 0.29 104.12 ± 0.23 104.12 ± 0.79106.78 ± 4.64 105.41 ± 0.60 5% 3M 257 (1%) 100.29 ± 0.12 104.36 ± 0.18104.98 ± 2.41 102.31 ± 0.46 102.42 ± 0.10 103.16 ± 0.37 105.79 ± 0.27107.09 ± 1.63 103.76 ± 3.59 197 96.81 ± 0.17 97.74 ± 0.20 99.22 ± 0.3399.28 ± 0.14 101.47 ± 0.22 102.69 ± 0.92 102.69 ± 0.92 100.39 ± 1.04101.11 ± 2.66 183 97.69 ± 0.21 99.73 ± 0.32 99.43 ± 2.77 99.61 ± 0.33100.01 ± 0.05 100.80 ± 1.07 103.70 ± 1.58 100.75 ± 1.82 102.19 ± 1.33245 182 96.76 ± 0.25 102.01 ± 0.01 98.46 ± 0.15 99.00 ± 0.12 98.07 ±0.10 101.48 ± 0.27 104.39 ± 1.55 102.91 ± 1.16 99.21 ± 4.25 189 98.73 ±0.19 100.72 ± 0.17 99.20 ± 0.25 184 100.09 ± 0.08 101.71 ± 0.14 96.86 ±0.20 193 188 100.28 ± 0.02 99.39 ± 0.17 97.04 ± 0.21 195 99.39 ± 0.3299.33 ± 0.07 97.84 ± 0.25 101.13 ± 0.10 103.13 ± 0.10 103.00 ± 0.15106.25 ± 0.99 106.84 ± 1.38 106.28 ± 1.22 255 98.87 ± 0.42 100.67 ± 0.0298.73 ± 0.13 256 97.58 ± 0.03 100.06 ± 0.22 98.05 ± 0.12 99.74 ± 0.0799.28 ± 0.24 101.74 ± 0.37 101.71 ± 0.44 105.42 ± 2.10 105.55 ± 3.20Graceway 98.62 ± 0.11 102.32 ± 0.28 96.66 ± 0.18 101.65 ± 0.06 101.02 ±0.10 103.58 ± 0.19 103.64 ± 0.15 101.70 ± 0.79 103.20 ± 1.85 Aldara  ®5% Imiquimod 110 101.06 ± 0.35 102.17 ± 0.95 99.48 ± 0.19 101.46 ± 0.0999.03 ± 0.14 102.73 ± 0.64 103.36 ± 0.38 102.42 ± 1.16 102.38 ± 2.82*116 98.63 ± 0.25 99.15 ± 0.13 96.87 ± 0.09 117 99.00 ± 0.73 102.06 ±0.10 98.42 ± 0.09 250 97.67 ± 0.11 101.88 ± 0.06 99.37 ± 1.05 99.43 ±0.20 99.74 ± 0.13 101.57 ± 0.35 105.32 ± 2.42 102.45 ± 0.50 101.14 ±2.23 254 96.29 ± 0.27 99.75 ± 0.09 97.11 ± 0.25 120 99.79 ± 0.27 100.61± 0.03 98.82 ± 0.17 121 235 99.25 ± 0.25 102.80 ± 0.20 100.78 ± 0.11 12399.71 ± 0.17 101.49 ± 0.10 99.52 ± 0.34 102.08 ± 0.34 101.11 ± 0.27103.27 ± 0.31 102.35 ± 0.47 105.49 ± 1.11 103.34 ± 1.44 124 93.17 ± 0.0794.26 ± 0.04 92.93 ± 0.14 125 98.37 ± 0.23 102.33 ± 0.29 99.14 ± 0.1499.99 ± 0.21 100.38 ± 0.09 103.28 ± 0.76 104.87 ± 2.65 102.48 ± 1.27103.87 ± 1.37 126 102.37 ± 0.58 102.84 ± 0.45 104.11 ± 0.04 100.02 ±0.95 101.32 ± 0.40 99.28 ± 3.25 98.43 ± 0.55 101.95 ± 0.37 103.02 ± 1.89PBO4 0 ± 0   0 ± 0   0 ± 0   0 ± 0   0 ± 0   0 ± 0   0 ± 0   0 ± 0   0 ±0 PBO1 0 ± 0   0 ± 0   0 ± 0   0 ± 0   0 ± 0   0 ± 0   0 ± 0   0 ± 0   0± 0 PBO2 0 ± 0   0 ± 0   0 ± 0   0 ± 0   0 ± 0   0 ± 0   0 ± 0   0 ± 0  0 ± 0 PBO3 0 ± 0   0 ± 0   0 ± 0   0 ± 0   0 ± 0   0 ± 0   0 ± 0   0 ±0   0 ± 0 *30° C. sample analysed, as 40° C. had shown signs of phaseseparation.

(2) Stability of Benzyl Alcohol in Formulations

In Table 21, Benzyl alcohol content is found to fall over the durationof the stability tests. The greatest loss observed is in the placebo's;Pbo4 (1.08±0.02% w/w), Pbo1 (1.01±0.03% w/w), Pbo2 (1.04±0.08% w/w) andPbo3 (1.11±0.00% w/w) and the active formulation 257 (1%) (1.37±0.01%w/w) which shows a loss in benzyl alcohol at about 40° C. for about 6months down from 2.0% w/w. The specified range for benzyl alcohol in theAldara® 5% imiquimod cream formulations (1.0 to 2.1% w/w), are withinspecification for Aldara® 5% imiquimod cream. The decrease in benzylalcohol content from the formulations is possibly the result of theformation of an ester (benzyl isostearate), whereby there is a reactionbetween the excipients of benzyl alcohol and isostearic acid.

TABLE 21 Amount of Benzyl Alcohol that is Recovered from theFormulations when the formulations that are Stored at 25° C. and 40° C.over a 6 Month Period. Highlighted Grey Areas Indicate Time Points WhichAre Not Tested Due To Rejection/Omission Of Formulations (N = 3 ± Sd).Imiquimod T-0 T-1 month 25° C. T-1 month 4° C. T-2 months 25° C. T-2months 40° C. T-3 months 25° C. T-3 months 40° C. T-6 months 25° C. T-6months 40° C. Formulations Mean SD Mean SD Mean SD Mean SD Mean SD MeanSD Mean SD Mean SD Mean SD Aldara ® 2.11 ± 0.02 2.04 ± 0.01 1.86 ± 0.012.04 ± 0.01 1.84 ± 0.06 1.88 ± 0.02 1.67 ± 0.02 1.76 ± 0.05 1.41 ± 0.005% 3M 257 (1%) 2.06 ± 0.01 2.01 ± 0.01 1.74 ± 0.02 2.00 ± 0.04 1.07 ±0.03 1.74 ± 0.01 1.37 ± 0.01 1.58 ± 0.01 1.02 ± 0.08 197 2.06 ± 0.002.06 ± 0.01 1.86 ± 0.01 2.05 ± 0.00 1.91 ± 0.02 1.85 ± 0.01 1.70 ± 0.021.74 ± 0.05 1.47 ± 0.02 183 2.05 ± 0.01 2.01 ± 0.01 1.85 ± 0.12 2.00 ±0.01 1.81 ± 0.00 1.78 ± 0.01 1.56 ± 0.02 1.66 ± 0.04 1.24 ± 0.01 245 1822.17 ± 0.00 2.17 ± 0.00 1.95 ± 0.01 2.11 ± 0.04 1.97 ± 0.00 1.94 0.011.82 ± 0.04 1.85 ± 0.03 1.48 ± 0.05 189 2.11 ± 0.01 2.06 ± 0.02 1.88 ±0.02 184 2.13 ± 0.01 2.09 ± 0.01 1.86 ± 0.01 193 188 2.15 ± 0.02 2.05 ±0.02 1.84 ± 0.01 195 2.12 ± 0.02 2.04 ± 0.01 1.85 ± 0.02 2.07 ± 0.031.95 ± 0.03 1.88 ± 0.01 1.74 ± 0.02 1.80 ± 0.01 1.48 ± 0.01 255 2.09 ±0.01 2.04 ± 0.00 1.81 ± 0.02 256 2.07 ± 0.01 2.05 ± 0.00 1.85 ± 0.002.06 ± 0.02 1.87 ± 0.03 1.84 ± 0.01 1.88 ± 0.01 1.76 ± 0.01 1.46 ± 0.01Graceway 2.06 ± 0.01 2.06 ± 0.00 1.80 ± 0.00 2.05 ± 0.00 1.91 ± 0.021.87 ± 0.02 1.65 ± 0.01 1.73 ± 0.00 1.38 ± 0.03 Aldara  ® 5% Imiquimod110 2.09 ± 0.01 2.04 ± 0.01 1.84 ± 0.01 2.04 ± 0.02 1.91 ± 0.02 1.87 ±0.02 1.75 ± 0.01 1.78 ± 0.04 1.72 ± 0.02 116 2.08 ± 0.01 2.05 ± 0.011.87 ± 0.01 117 2.11 ± 0.01 2.06 ± 0.01 1.82 ± 0.05 250 2.03 ± 0.01 2.00± 0.01 1.78 ± 0.07 1.96 ± 0.02 1.70 ± 0.01 1.74 ± 0.01 1.47 ± 0.03 1.59± 0.02 1.12 ± 0.02 254 2.07 ± 0.01 2.04 ± 0.01 1.89 ± 0.01 120 2.11 ±0.00 2.00 ± 0.01 1.77 ± 0.02 121 235 2.10 ± 0.00 2.10 ± 0.02 1.92 ± 0.02123 2.11 ± 0.01 2.05 ± 0.00 1.82 ± 0.01 2.06 ± 0.01 1.85 ± 0.01 1.84 ±0.01 1.59 ± 0.00 1.73 ± 0.02 1.34 ± 0.01 124 1.96 ± 0.01 1.89 ± 0.011.71 ± 0.00 125 2.08 ± 0.01 2.06 ± 0.01 1.82 ± 0.00 2.02 ± 0.01 1.82 ±0.00 1.85 ± 0.00 1.63 ± 0.04 1.73 ± 0.02 1.32 ± 0.02 126 2.00 ± 0.022.02 ± 0.01 1.89 ± 0.01 1.86 ± 0.02 1.65 ± 0.02 2.00 ± 0.04 1.70 ± 0.042.01 ± 0.03 1.55 ± 0.02 PBO4 1.93 ± 0.02 1.83 ± 0.08 1.90 ± 0.03 1.91 ±0.01 1.53 ± 0.00 1.81 ± 0.01 1.39 ± 0.01 1.71 ± 0.01 1.08 ± 0.02 PBO11.82 ± 0.01 1.65 ± 0.00 1.85 ± 0.09 1.54 ± 0.10 1.93 ± 0.03 1.55 ± 0.041.58 ± 0.02 1.01 ± 0.03 PBO2 1.83 ± 0.01 1.65 ± 0.01 1.87 ± 0.19 1.70 ±0.09 2.01 ± 0.13 1.61 ± 0.08 1.65 ± 0.05 1.04 ± 0.08 PBO3 1.97 ± 0.011.81 ± 0.01 2.09 ± 0.00 1.81 ± 0.00 2.12 ± 0.04 1.70 ± 0.00 1.73 ± 0.011.11 ± 0.00 *30° C. sample analysed, as 40° C. had shown signs of phaseseparation.

(D) Microscopic Stability of the Formulations

In Table 22, there is no change in the particle size in any of theformulations tested at about 25° C. over about a 6 month period. Inaddition, and with reference to the microscopic photographs presented inFIGS. 8A-C and 9; no crystals are detected. For completeness andreference, the pictures of the formulations rejected after one monthstability are shown in FIGS. 10A-B.

TABLE 22 Results of Particle Size of the Formulations when viewed undera Microscope at 25° C. over a 6 Month Period. Particle size (μM) t = 1 t= 2 t = 3 t = 6 Formulation T = 0 Month Months Months Months 3M Aldara ®5% <10 <10 <10 <10 <10 GRACEWAY <10 <10 <10 <10 <10 Aldara ® 5% 257 <10<10 <10 <10 <10 (1%) 110 <10 <10 <10 <10 <10 250 <10 <10 <10 <10 <10 182<10 <10 <10 <10 <10 195 10 10 10 10 10 123 10 10 10 10 10 125 10 10 1010 10 256 10 10 10 10 10 197 10 10 10 10 10 183 10 10 10 10 10 126 <10<10 <10 <10 <10 Pbo1 <10 <10 <10 <10 <10 Pbo2 <10 <10 <10 <10 <10 Pbo3<10 <10 <10 <10 <10 Pbo4 <10 <10 <10 <10 <10

(F) Macroscopic Stability of the Formulations

In Table 23, there are no obvious physical changes in' the formulationsthat are tested over the six month stability program, with the exceptionof the placebos, which become notably less viscous. See also Tables24-26.

TABLE 23 Macroscopic Appearance when Imiquimod Formulations are storedat about 25° C. over a 6 Month Period. Appearance spatula Test (25° C.sample only) Visual Viscosity (25° C. sample only) Imiquimod t = 1 t = 2t = 3 t = 6 t = 1 t = 2 t = 3 t = 6 Formulation t = 0 month monthsmonths months t = 0 month months months months 3M Glossy, Glossy,Glossy, Glossy, Glossy, High Medium Medium Medium Medium Aldera ® veryvery very very very High High 5% smooth smooth smooth smooth smoothImiquimod Graceway Glossy, Glossy, Glossy, Glossy, Glossy, High HighMedium High Medium Aldera ® very very very very very High 5% smoothsmooth smooth smooth smooth Imiquimod 257(1%) Glossy, Glossy, Glossy,Glossy, Glossy, Medium Medium Medium Medium Low And and very very veryHigh High High Viscoscity smooth smooth smooth smooth smooth 110 Glossy,Glossy, Glossy, Glossy Glossy, High High High High Medium very veryslightly slightly slightly slightly slightly textured Textured texturedtextured textured 250 Glossy Glossy Glossy, Glossy, Glossy, MediumMedium Medium Medium Medium and and very very very High High Highsmooth, textured slightly slightly slightly some textured texturedtextured aeration 182 Very Very Very Very Very High Medium Medium MediumHigh glossy glossy glossy glossy glossy High High High and and and andand smooth smooth smooth smooth smooth 195 Glossy, Glossy, Glossy,Glossy, Glossy, High High Medium Medium High slightly slightly veryslightly slightly High High textured textured slightly textured texturedtextured 123 Glossy, Glossy, Glossy Glossy, Glossy, Medium Medium MediumHigh Medium and slightly slightly slightly slightly High High Highsmooth textured textured, textured, textured smoothed smoothed OUT OUT124 Glossy Glossy Glossy, Glossy, Glossy, Medium Medium Medium MediumLow and and smooth smooth slightly High smooth smooth with texturedslight aeration 256 Glossy, Glossy, Glossy, Glossy, Glossy, MediumMedium Medium Medium High slightly slightly slightly slightly slightlyHigh High High High textured textured textured textured textured 197Glossy, Glossy, Glossy Glossy Glossy Medium Medium High High Highslightly very and and and High textured slightly textured slightlyslightly textured textured textured 183 Glossy, Glossy Glossy GlossyGlossy High Medium Medium Medium Low smooth and and and and High HighHigh slight smooth smooth smooth smooth aeration 126 Glossy, Smooth,Glossy Slightly Glossy Medium Medium Medium Medium Low very slightly andtextured, Viscosity slightly textured, smooth sheen textured glossy Pbo1Glossy Very Very Very Glossy Low Medium Medium Low Low and glossy glossyglossy and Low Low smooth and and and smooth smooth smooth smooth Pb02Glossy Glossy Glossy, Glossy Glossy Medium Medium Medium Medium Low andand and very and Low Low Low smooth smooth smooth slightly smoothtextured Pb03 Glossy Glossy Glossy, Glossy, Glossy Low Medium MediumMedium Medium and and very very and Low Low Low smooth smooth slightlyslightly smooth textured textured but but smoothed smoothed out out Pb04Glossy Glossy Glossy Glossy Smooth Medium Medium Medium Low Low and andand and cream Low Low smooth smooth smooth smooth high sheen

TABLE 24 Stability Data for 10 Formulations, i.e., Formulations 116,117, 120, 124, 188, 184, 189, 235, 254 and 255, rejected after 1 MonthStability, with respect to the Spatula Test, Visual Viscosity andParticle size (as determined by microscopy). Majority of particleSpatula Test Visual Viscosity size (μM) T = 1 T = 1 T = 1 Formulation T= 0 Month T = 0 Month T = 0 Month 116 Glossy, Glossy, Medium Medium- 1010 textured textured High 117 Glossy, Glossy, Medium- Medium- <10 <10slightly slightly High High textured textured 254 Smooth Smooth, HighMedium- <10 <10 with matt matt High appearance 120 Smooth, Smooth, VeryVery <10 <10 matt matt High High appearance, some aeration 235 Glossy,Glossy, Medium- Medium <50 <50 textured very Low but slightly doestextured smooth but does out smooth out 188 Glossy Glossy Medium- High<10 <10 and and Low textured textured 189 Glossy, Glossy, High Very <10<10 very slightly High slightly textured textured 184 Glossy, Glossy,High High <10 <10 slightly slightly textured textured 255 Glossy andGlossy and High High 10 <10 smooth smooth 124 Glossy, Glossy, Medium-Medium- <10 <10 very very High High slightly slightly textured textured

TABLE 25 pH Stability Data for 10 Imiquimod Formulations, i.e.,Formulations 116, 117, 120, 124, 188, 184, 189, 235, 254 and 255,Rejected after 1 Month Stability. Formulation pH Identity T = 0 T = 1Month 116 5.0 4.7 117 4.5 4.5 254 4.7 4.7 120 4.5 4.5 235 4.5 4.5 1884.7 4.7 189 4.7 4.7 184 4.7 4.7 255 4.5 4.5 124 4.5 4.5

TABLE 26 Viscosity Stability Data for 10 Imiquimod Formulations, i.e.,Formulations 116, 117, 120, 124, 188, 184, 189, 235, 254 and 255,Rejected after 1 Month Stability Brookfield (cps) Bohlin Viscosity (cps)Formulation Crossover G′ T = 1 T = 1 Identity T = 0 T = 0 T = 0 Month T= 0 Month 116 9.0 478 601867 63500 15350 13300 117 14.0 1151 12166671281000 17250 15600 254 10.3 1399 1476667 1423000 19050 19000 120 15.3884 1416667 1393000 20250 20900 235 6.0 134 245333 313000 6350 5700 18814.0 708 1141333 1254000 20350 20750 189 34.8 1037 1344333 1463000 1870018550 184 23.0 1054 1475667 1350000 20200 21600 255 16.0 1488 24833331334000 21150 25150 124 7.0 561 849000 663000 14400 14250

(F) Brookfield Viscosity Stability Results of Formulations

In Table 27, Brookfield viscosity measurements are notoriously variableand, as such, there are fluctuations in the measurements of theformulations over about a 6 month period when stored at about 25° C.Variations in results are further observed if the spindle or the speedof the spindle rotation is altered. Although the majority of theformulations are measured using the same settings and spindle; theplacebo formulations (Pbo1, Pbo2, Pbo3 and Pbo4) result in torquemeasurements below the threshold required for accurate measurements andsubsequently readings are inaccurate. Attempts are made to change thesettings and spindles; however, results are vastly different and thusunreliable. See also Tables 24-26.

TABLE 27 Viscosity and Rheology Measurements of Imiquimod Formulationsstored at 25° C. over 6 Month Period. Cross- Bohlin Viscosity (cPs)Form- over Brookfield (cPs) (based on 3M method) ulation G(Pa) (o) t = 1t = 2 t = 3 t = 6 t = 1 t = 2 t = 3 t = 6 Identity t = 0 t = 0 t = 0Month Months Months Months t = 0 Month Months Months Months 3M 507 123660333 623000 337000 428833 166233 15700 17300 17600 13296 12833Aldera ® 5% Imiquimod Graceway 716 10.5 1108667 1109000 587667 768566252033 18250 20250 19900 18697 15100 Aldera ® 5% Imiquimod 257(1%) 35210.52 642667 600000 220333 351566 * 13600 15050 11500 6075 3139 110 78211.5 87100 119000 782333 619300 366067 16250 16400 18000 16368 14076 250320 9 695333 816000 557333 394166 141400 13700 16400 14950 10587 5890182 702 8.5 693067 1097000 904667 523033 273233 18050 17850 18550 1682013691 195 692 15 1141333 1293000 779333 618133 381700 17000 17600 1650016208 14696 123 510 10.8 804000 773000 386333 701500 199933 15800 1625015200 13095 9587 125 485 8.5 603000 707000 429667 412133 127067 1490017050 15300 12069 8301 256 667 7.3 1126000 958000 697667 757523 24950019400 18300 18750 15453 12379 197 646 14 1082667 1377000 613667 607366274400 17750 17850 17600 15861 13524 183 719 10.3 693333 839000 596000332900 188000 18700 19100 18600 15906 12120 126 AP 430100 235066 228104212500 105720 16783 12739 14749 10856.5 8789.5 PB01 306 11 85000 * * * *12100 14450 7500 7969 2508.3 PB02 263 13 79500 14200 13950 9100 6452.52617.6 PB03 305 11.5 117000 12200 13850 9000 8395 3256.5 PB05 227800 *10350 7953 5511 3550 2247 Results un-reliable and not presented as thetorque was out of range (due to low viscosity) for the Brookfieldviscometer using the settings and spindle used for all the othersamples. Alternative spindles and settings were investigated; however,the results were vastly different than previous readings. ** No recordedmeasurements, as test was only required for initial formulations choiceand development.

(G) Bohlin Viscosity Results

Also as shown in Table 27, the Bohlin viscosity results are in contrastto the results of the Brookfield viscosity and appear to be moreconsistent for all formulations. A fall in the viscosity is observed for257 (1%) and placebo formulations, Pbo1-4, over the 6 month stabilitystudy, whereby the viscosity falls by approximately 50%. Allformulations are within the range of the specifications for the Aldara®5% imiquimod cream formulation (2000 to 35,000 cps), See also Tables24-26.

(H) pH Stability of Formulations

in Table 28, it reports that the specification for all formulations thatare tested, fall within the Aldara® 5% imiquimod cream specifications(pH 4.0 to 5.5). A slight variation in pH is observed over the 6 monthperiod for all of the formulations. See also Tables 24-26.

TABLE 28 ph for Imiquimod Formulations when Stored at about 25° C. andabout 40° C. over a 6 Month Period. Grey Areas Indicate No Test IsPerformed. PH t = 0 t = 1 month t = 2 months t = 3 months t = 6 monthsFormulation 25° C. 25° C. 40° C. 25° C. 40° C. 25° C. 40° C. 25° C. 40°C. 3m Aldara ® 5% 4.5 4.5 4.5 4.5 4.5 4.7 4.3 4.1 Imiquidod GracewayAldara ® 4.5 4.5 4.5 4.5 4.5 4.5 4.3 4.5 5% Imiquidod 257 (1%) 4.2 4.54.5 4.5 4.5 4.1 4.1 3.9 110 5   4.7 4.7 4.7 4.7 4.4 4.5  4.3* 250 4.24.2 4.2 4.5 4.2 4   4.2 4.1 182 4.5 4.5 4.5 4.5 4.5 4.6 4.3 4.3 195 4.74.5 4.5 4.5 4.5 4.7 4.5 4.5 123 4.5 4.7 4.7 4.7 4.7 4.3 4.1 4.3 125 4.54.5 4.5 4.5 4.5 4.2 4.1 4.1 256 4.7 4.7 4.7 4.7 4.7 4.4 4.3 4.3 197 4.54.7 4.7 4.7 4.7 4.6 4.5 4.3 183 4.5 4.5 4.5 4.5 4.5 4.2 4.5 4.1 126 4.24.3 4.3 4.3 4.3 4.3 4.3 4.1 4.1 Pbo1 4.5 4.5 4.5 4.5 4.2 4.5 4.0 4.0Pbo2 4.5 4.5 4.2 4.1 4.2 4.2 4.1 4.1 Pbo3 4.5 4.5 4.2 4.2 4.2 4.2 4.24.2 Pho4 4.5 4.2 4.5 4.2 4.2 4.1 4.1 4.0 4.0 *30° C. sample analyzed asthe 40° C. sample had phase separated

(I) Preservative Efficacy Test

Table 29 reports final viable counts of organism inoculations that areadded to the formulations.

TABLE 29 Total Viable Counts that are obtained for the OrganismInoculates into the Imiquimod Formulations Mimi for 182 and Cfu/ml for126 and Organism 110 Pbo4 Staphylococcus aureus 2.4E+08 3.1E+08Escherichia coli 1.7E+08 2.1E+08 Pseudomonas 9.0E+07 1.1E+08 aeruginosaCandida albicans 1.0E+08 1.1E+08 Aspergillus niger 1.7E+07 1.6E+08

Table 30 shows colony forming unit count (cfu) for Staphylococcus aureusafter PET validation is performed on two formulations stored at about2-8° C.

TABLE 30 Viable counts that are obtained for Staphylococcus aureus thatare Inoculated Formulations after PET Validation Imiquimod SuspensionViable count Formulation fluid Dilution (cfu/ml) 110 DIE broth 1 ml in 9ml 2.20E+08 0.1 ml in 0.9 ml 2.80E+08 Ringer's 1 ml in 9 ml 1.00E+03solution 0.1 ml in 0.9 ml 1.50E+03 182 D/E broth 1 ml in 9 ml 2.30E+080.1 ml in 0.9 ml 2.60E+08 Ringer's 1 ml in 9 ml 1.00E+03 solution 0.1 mlin 0.9 ml 1.40E+03

The preservative efficacy test (“PET”) is a procedure used todemonstrate antimicrobial activity of a formulation with respect to thepreservative system used. In Table 31, cell counts that are recoveredfrom the inoculated formulations at various time points are reported.The data shows that sufficient log reductions are present in theformulations at about 2-8° C. and about 40° C. and meet the requirementsthat are specified in both the USP and EP.

TABLE 31 Colony Forming Unit Counts that are recovered (Cfu/MI) for EachOrganism from the Imiquimod Formulations over 28 Days. Organismsrecovered-(cfu/ml) Pass/ Formulation Organism 0 h 24 h 48 h 7 days 19days 21 days 28 days Fail Pho4 S. aureus 3.10E+05 0.00E+00 0.00E+000.00E+00 0.00E+00 0.00E+00 0.00E+00 PASS STORAGE: E. coil 5.00E+030.00E+00 0.00E+00 0.00E+00 0.00E+00 0.00E+00 0.00E+00 PASS 2-8° C. Ps.aeruginosa 9.00E+03 0.00E+00 0.00E+00 0.00E+00 0.00E+00 0.00E+000.00E+00 PASS A albican 5.00E+04 1.80E+03 0.00E+00 0.00E+00 0.00E+000.00E+00 0.00E+00 PASS A. niger 1.60E+05 6.00E+03 2.50E+03 0.00E+000.00E+00 0.00E+00 0.00E+00 PASS Pho4 S. aureus 1.70E+06 0.00E+000.00E+00 0.00E+00 0.00E+00 0.00E+00 0.00E+00 PASS STORAGE: E. coil6.00E+03 0.00E+00 G.00E+00 0.00E+00 0.00E+00 0.00E+00 0.00E+00 PASS 40°C. Ps. aeruginosa 1.30E+04 0.00E+00 0.00E+00 0.00E+00 0.00E+00 0.00E+000.00E+00 PASS C albican 2.60E+04 4.10E+03 1.30E+03 0.00E+00 0.00E+000.00E+00 0.00E+00 PASS A. niger 3.00E+05 1.70E+04 3.30E+03 0.00E+000.00E+00 0.00E+00 0.00E+00 PASS 126 S. aureus 5.70E+04 0.00E+00 0.00E+000.00E+00 0.00E+00 0.00E+00 0.00E+00 PASS STORAGE: E. coil 1.20E+060.00E+00 0.00E+00 0.00E+00 0.00E+00 0.00E+00 0.00E+00 PASS 2-8° C. Ps.aeruginosa 1.40E+04 0.00E+00 0.00E+00 0.00E+00 0.00E+00 0.00E+000.00E+00 PASS C albican 3.50E+04 5.00E+03  400E+02 0.00E+00 0.00E+000.00E+00 0.00E+00 PASS A. niger 1.00E+05 2.10E+04 2.50E+03 0.00E+000.00E+00 0.00E+00 0.00E+00 PASS 126 S. aureus 2.10E+04 0.00E+00 0.00E+000.00E+00 0.00E+00 0.00E+00 0.00E+00 PASS STORAGE: E. coil 5.00E+050.00E+00 0.00E+00 0.00E+00 0.00E+00 0.00E+00 0.00E+00 PASS 40° C. Ps.aeruginosa 1.50E+04 0.00E+00 0.00E+00 0.00E+00 0.00E+00 0.00E+000.00E+00 PASS C albican 3.80E+04 3.60E+03 2.50E+03 0.00E+00 0.00E+000.00E+00 0.00E+00 PASS A. niger 1.00E+05 2.90E+03 1.60E+03 0.00E+000.00E+00 0.00E+00 0.00E+00 PASS 110 S. aureus 1.00E+06 0.00E+00 0.00E+000.00E+00 0.00E+00 0.00E+00 0.00E+00 PASS STORAGE: E. coil 7.00E+050.00E+00 0.00E+00 0.00E+00 0.00E+00 0.00E+00 0.00E+00 PASS 2-FPG Ps.aeruginosa 8.00E+04 0.00E+00 0.00E+00 0.00E+00 0.00E+00 0.00E+000.00E+00 PASS C albican 8.00E+05 2.60E+04 7.00E+03 7.00E+01 0.00E+000.00E+00 0.00E+00 PASS A. niger 6.00E+04 9.00E+04 2.30E+04 7.00E+033.70E+02 0.00E+00 0.00E+00 PASS 110 S. aureus 6.00E+05 0.00E+00 0.00E+000.00E+00 0.00E+00 0.00E+00 0.00E+00 PASS STORAGE: E. coil 8.00E+040.00E+00 0.00E+00 0.00E+00 0.00E+00 0.00E+00 0.00E+00 PASS 40° C. Ps.aeruginosa 7.00E+05 0.00E+00 0.00E+00 0.00E+00 0.00E+00 0.00E+000.00E+00 PASS C albican 1.60E+05 1.50E+04 4.00E+03 2.20E+02 0.00E+000.00E+00 0.00E+00 PASS A. niger 7.00E+04 6.00E+04 2.50E+03 1.90E+041.90E+02 0.00E+00 0.00E+00 PASS 182 S. aureus 1.70E+06 0.00E+00 0.00E+000.00E+00 0.00E+00 0.00E+00 0.00E+00 PASS STORAGE: E. coil 1.70E+060.00E+00 0.00E+00 0.00E+00 0.00E+00 0.00E+00 0.00E+00 PASS 2-8° C. Ps.aeruginosa 7.00E+05 0.00E+00 0.00E+00 0.00E+00 0.00E+00 0.00E+000.00E+00 PASS C albican 3.00E+05 2.10E+04 1.90E+03 3.00E+03 0.00E+000.00E+00 0.00E+00 PASS A. niger 4.00E+05 5.00E+03 2.40E+03 3.00E+030.00E+00 0.00E+00 0.00E+00 PASS 182 S. aureus 1.50E+06 0.00E+00 0.00E+130 0.00E+00 0.00E+00 0.00E+00 0.00E+00 PASS STORAGE: E. coil1.10E+06 0.00E+00 0.00E+00 0.00E+00 0.00E+00 0.00E+00 0.00E+00 PASS 40°C. Ps. aeruginosa 6.00E+05 0.00E+00 0.00E+00 0.00E+00 0.00E+00 0.00E+000.00E+00 PASS C albican 7.00E+05 3.00E+04 3.00E+03 7.00E+03 0.00E+000.00E+00 0.00E+00 PASS A. niger 7.00E+05 6.00E+03 2.70E+03 1.70E+031.20E+02 0.00E+00 0.00E+00 PASS

(J) Test Item Release Studies Through Synthetic Membranes

In FIG. 3, it indicates that there is a trend between the concentrationsof imiquimod present in the formulation as compared to the amount thatis released. This is supported by the results presented in FIG. 4 andthe corresponding statistical analysis, where it can be seen that thatthe higher the imiquimod concentration in the formulation, the greaterthe release of imiquimod. However, formulation 183 (3.75% w/w imiquimod)gives a statistically (at a 95% confidence level) greater cumulativerelease of imiquimod when it is compared to the 2.5% w/w formulations.All of the 5% w/w formulations, i.e., Aldara® 5% imiquimod cream batch,Aldara® 5% imiquimod cream Graceway batch, and Aldara® 5% imiquimodcream Sachet), result in significantly (p<0.05) higher amounts ofimiquimod released over a 3 h time period in comparison to 1%, 2.5% and3.75% w/w imiquimod formulations. There is no statistical difference(p>0.05) in the total cumulative amount of imiquimod that is releasedfrom any of the 3.75% w/w imiquimod formulations; likewise there is alsono statistical difference (p>0.05) from the 2.5% w/w imiquimodformulations.

ANOVA statistical analysis (95% confidence level): mean total cumulativeamount that is released (μ/cm²) after 3 h (from results that arepresented in FIG. 3):

Source DF SS MS F P Formulation 12 86439222 7203268 19.40 0.000 Error 3914484370 371394 Total 51 100923592 S = 609.4 R-Sq = 85.65% R-Sq (ad) =81.23% Individual 95% CIs For Mean Based on Pooled StDev Level N MeanSt. Dev +------------ +------------ +------------ +------------ Aldara3M 5% 4 5332.8 734.2 (---*---) Aldara sachet 4 4605.5 626.9 (---*---)110 4 1862.8 185.9 (---*---) 250 4 1845.6 206.4 (---*---) 182 4 3161.3774.9 (---*---) 195 4 3046.2 998.2 (---*---) 123 4 2094.9 674.6(---*---) 125 4 2134.1 369.0 (---*---) 256 4 2918.7 59.5 (---*---) 197 42766.0 929.1 (---*---) 183 4 3453.2 564.4 (---*---) MedPharm Aldara 44813.3 660.7 (---*---) 257% 4 586.9 170.2 (---*---) +------------+------------ +------------ +------------ 0 1500 3000 4500 Pooled StDev= 609.4

ANOVA statistical analysis (95% confidence level): mean total cumulativeamount that is released (ug/cm2) after 3 h for each concentration ofimiquimod in the formulations that are tested (from results that arepresented in FIG. 4):

Source DF SS MS F P Formulation 3 83957708 27985903 79.18 0.000 Error 4816965878 353456 Total 51 100923592 S = 594.5 R-Sq = 83.19% R-Sq (adj) =82.14% Individual 95% CIs For Mean Based on Pooled StDev Level N MeanSt. Dev +------------ +------------ +------------ +------------   1% 4586.9 170.2 (---*---) 2.50% 16 1984.4 389.9 (-*-) 3.75% 20 3069.1 702.3(*-) 5.00% 12 4917.2 689.4 (--*-) +------------ +------------+------------ +------------ 0 1500 3000 4500 Pooled StDev = 594.5

The result for the rate of release presented in Table 32, indicate thatthe higher the amount of imiquimod in the formulation, the faster therate of release of imiquimod. Similar to the results of the cumulativeamount permeated, there is no statistical difference (p>0.05) betweenthe results for the 2.5% w/w in imiquimod formulations (Table 32 andFIG. 12) and likewise for the 3.75% w/w imiquimod formulations (Table 32and FIG. 13). See also FIGS. 11 and 14.

TABLE 32 Comparison of Mean Flux of Imiquimod (pg/Cm2) over a 3 11Period for Membrane Release Tests (Mean ± Sd, Where N = 4) that arePresented as a Function of Time from 15 Min To 3 H. Flux ✓timeFormulations Mean ± sd Graceway Aldara ® 5% 3720.65 ± 569.38 imiquimod3M Aldara° 5% Imiquimod 3873.38 ± 479.64 Cream Bulk 3M Aldara 5%Imiquimod 3319.56 ± 494.32 Cream sachet 257 (1%)  504.40 ± 148.43 123(2.5%) 1539.39 ± 482.36 250 (2.5%) 1396.68 ± 173.65 125 (2.5%) 1592.98 ±324.51 110 (2.5%) 1518.29 ± 151.17 182 (3.75%) 2410.03 ± 599.08 195(3.75%) 2310.06 ± 597.59 256 (3.75%) 2424.87 ± 28.09 197 (3.75%) 2116.53± 723.60 183 (3.75%) 2516.84 ± 357.41

ANOVA statistical analysis (95% confidence level): mean amount ofimiquimod released (μ/cm²) over a 3 hour period for the membrane releasestudies (mean±sd, where n=4) presented as a function of √time from 15min to 3 h (from results presented in Table 32):

Source DE SS MS F P Formulation 12 45353042 3779420 19.05 0.000 Error 3977392670 198443 Total 51 53092309 S = 445.5 R-Sq = 85.42% R-Sq (adj) =80.94% Individual 95% CIs For Mean Based on Pooled StDev Level N MeanSt. Dev +------------   +------------   +------------   +------------ 3MAldara ® 5% 4 3873.4 479.6                    (--*---) Imiquimod CreamBulk 3M Aldara ® 5% 4 3319.6 494.3                  (---*--) ImiquimodCream Sachet 110 4 1518.3 151.2        (---*--) 250 4 1396.7 173.6      (---*--) 182 4 2410.0 599.1            (---*---) 195 4 2310.1597.6           (---*---) 123 4 1539.4 482.4        (---*---) 125 41593.0 324.5         (--*---) 256 4 2424.9 28.1           (---*---) 1974 2116.5 723.6          (---*--) 183 4 2516.8 357.4            (---*---)Graceway ® 5% 4 3720.6 569.4                  (---*---) Imiquimod Cream257 1% 4 504.4 148.4 (---*---) +------------   +------------  +------------   +------------ 0    1200    2400     3600 Pooled StDev =445.5

ANOVA statistical analysis (95% confidence level): Comparison of themean amount of imiquimod released (μg/cm²) over a 3 hour period for the3M Aldara® 5% imiquimod cream 1 kg batch, the 3M Aldara® 5% imiquimodcream sachet, the Graceway Aldara® 5% imiquimod cream 1 kg batch and257, 1% Imiquimod formulation (mean±sd, where n=4)—refer to FIG. 11:

Source DE SS MS F P Formulation 3 5737855 19126285 54.74 0.000 Error 124192460 349372 Total 15 61571315 S = 591.1 R-Sq = 93.19% R-Sq (adj) =91.49% Individual 95% CIs For Mean Based on Pooled StDev Level N MeanSt. Dev +------------   +------------   +------------   +------------ 3MAldara ® 5% 4 5332.8 734.2                     (---*---) Aldara sachet 44605.5 626.9                    (---*---) MedPharm Alara 4 4813.3 660.7                   (---*---) U2F 1% 4 586.9 170.2  (---*---)+------------   +------------   +------------   +------------0    1600    3200     4800 Pooled StDev = 591.1

ANOVA statistical analysis (95% confidence level): Comparison of themean amount of imiquimod released (μg/cm²) over a 3 hour period for 2.5%imiquimod formulations 123, 250, 125 and 110 (mean±sd, where n=4)—referto FIG. 12:

Source DE SS MS F P Formulation 3 274778 91593 0.55 0.659 Error 122004990 167083 Total 15 2279769 S = 408.8 R-Sq = 12.05% R-Sq (adj) =0.00% Individual 95% CIs For Mean Based on Pooled StDev Level N Mean St.Dev ---+----------+-----------+-----------+------- GW002 4 1862.8 185.9(---------------*---------------) GW008 4 1845.6 206.4(---------------*---------------) GW037 4 2094.9 674.6   (---------------*---------------) GW039 4 2134.1 369.0    (---------------*---------------) ---+---------+-----------+-----------+------- 1500  1800  2100  2400 PooledStDev = 408.8

ANOVA statistical analysis (95% confidence level): Comparison of themean amount of imiquimod released (μg/cm²) over a 3 hour period for3.75% imiquimod formulations 182, 195, 256, 197 and 183 (mean±sd, wheren=4)—refer to FIG. 13:

Source DE SS MS F P Formulation 4 1084063 271016 0.49 0.743 Error 158386917 552461 Total 19 9370981 S = 743.3 R-Sq = 11.57% R-Sq (adj) =0.00% Individual 95% CIs For Mean Based on Pooled StDev Level N Mean St.Dev -------+----------+------------+------------+-- GW030 4 3161.3 774.9   (---------------*---------------) GW033 4 3046.2 988.2   (---------------*---------------) GW040 4 2918.7 59.5  (---------------*---------------) GW041 4 2766.0 929.1(---------------*---------------) GW042 4 3453.2 564.4-------+----------+------------+------------+--2400   3000   3600   4200 Pooled StDev = 743.3

As discussed under FIG. 14 in the Brief Description of the Drawings,FIG. 14 shows a comparison of the mean amount of imiquimod released(μ/cm2) over a 3 hour period for the 2.5% (▴), 3.75% (s), 3M Aldara®imiquimod cream batch (▪), Graceway Aldara® imiquimod cream 1 kg batch(▪) and formulation 257 Imiquimod formulations (▪) (mean±sd, where n=4).

Based on the results; it appears that the greater the amount ofimiquimod in the formulation, the faster and greater the total amount ofimiquimod that is released, suggesting that the amount and rate ofrelease are concentration dependant.

(K) In vitro Skin Permeation Study

(1) Homogeneity

Manufacture of the formulations (about 100 g batches) is firstperformed, which batches are then mixed with the radioactive labelledmaterial. The batches are prepared by omitting about 1.38 g ofisostearic acid which is added with the radio-labelled imiquimod. Thehomogeneity of the test formulations, see Table 33, is measured asdescribed in under Homogeneity Control above and all compositions areconfirmed to meet the criterion (<10% CV).

TABLE 33 Homogeneity of Radioactivity for Imiquimod FormulationsFormulation % CV Graceway Aldara ® 5% 0.93 Imiquimod Cream 3M Aldara ®5% 1.50 Imiquimod Cream 182 0.80 195 2.39 256 1.17 197 0.07 183 1.54 1100.71 250 2.53 123 1.89 125 1.53 126 2.55 257 2.30 (1%)

(2) Franz Cell Study

The data that is shown in Table 34 is the actual amount of imiquimodthat is recovered for each formulation from the various matrices, whichis also represented graphically in FIG. 5. FIG. 6 represents the totalamount of imiquimod that is recovered for each formulation in theepidermis, dermis and receiver fluid combined.

TABLE 34 Amount of Imiquimod that is Recovered following Mass BalanceInvestigation Amount of imiquimod recovered ± SEM (ug) Formu- PercentageReplicates Receiver Unabsorbed Stratum Percentage total lationsimiquimod (n) Fluid Dose Corneum Epidermis Dennis recovered Graceway  5% 6 0.03 ±0.01 127.06 ±9.58 80.78 ±11.67 2.90 ±0.72 2.76 ±0.70 85.24±5.15 Aldara ® 5% Imiquimod Cream 3M   5% 4 0.05 0.03 132.75 ±17.6274.37 ±10.59 6.60 ±1.91 3.96 ±0.41 86.92 ±4.16 Aldara ® % ImiquimodCream 182 3.75% 3.75% 6 0.08 ±0.06 85.75 ±3.93 46.85 ±5.51 3.65 ±0.856.94 2.22 76.25 1.82 195 3.75% 3.75% 4 0.08 ±0.07 74.19 ±6.90 57.41±11.46 7.06 2.29 2.47 ±0.87 75.16 5.12 256 3.75% 3.75% 5 0.16 ±0.0671.73 ±7.22 33.41 ±4.77 1.99 ±0.71 9.03 ±2.37 61.91 3.95 197 3.75% 3.75%5 0.06 ±0.03 110.54 6.22 41.61 ±6.54 2.21 ±0.36 2.53 ±0.91 83.54 3.92183 3.75% 3.75% 4 0.02 ±0.01 113.84 ±11.63 40.99 ±6.99 3.26 ±0.53 5.11±2.32 86.66 6.68 110 2.5%  2.5% 6 0.00 ±0.00 52.92 3.96 33.96 ±3.43 3.25±0.70 2.32 ±0.44 73.82 4.64 250 2.5%  2.5% 5 0.00 ±0.00 82.46 ±2.9428.30 ±3.67 2.35 ±0.68 1.17 ±0.30 91.25 3.93 123 2.5%  2.5% 5 0.01 ±0.0168.33 ±3.18 35.93 ±10.40 4.20 ±1.69 1.80 ±0.32 88.04 7.95 125 2.5%  2.5%6 0.02 ±0.01 72.82 ±3.92 28.88 ±4.41 1.12 ±0.42 1.52 ±0.42 83.32 2.44126 2.5%  2.5% 5 0.01 ±0.00 64.00 ±5.27 29.59 ±4.97 2.36 ±0.40 4.44±1.62 80.15 6.61 257 1%   1% 4 0.01 ±0.00 28.88 ±4.60 12.49 ±3.75 0.42±0.14 1.54 ±1.05 86.98 3.40

The only data rejected from that presented in Table 34, FIG. 5 and FIG.6 are obvious outliers that are observed on the basis of cell failure.

The average data for the 5%, 1%, 3.75% and 2.5% w/w formulations showingthe amount of imiquimod that is recovered from the unabsorbed fraction,in the Stratum corneum and in the epidermis, dermis and receiver fluidcombined are shown in FIG. 7. This data shows that there is a lineardose release between the amount of imiquimod applied and recovery ineach of the matrices. See also Table 35 for stability of calibrationstandards in spent receiver fluid and Tables 36-40—for statisticalanalysis.

TABLE 35 Stability of Calibration Standards in Spent Receiver Fluid(Stored In HPLC Crimp Top Vials at Each Temperature (Where Recovery wasCompared To T = 0) 48 h % recovered in Spent Standard Spent receiverfluid (ug/ml) receiver fluid: Fridge RT 37° C. 105.5 Full thickness +88.242 88.546 91.704 84.4 placebo 84.561 84.421 85.629 52.75 91.77692.027 93.779 42.2 83.976 84.144 86.439 21.1 84.584 85.162 88.000 10.5588.307 86.897 90.798 5.275 90.260 87.973 86.134 105.5 Full thickness90.545 92.275 92.278 84.4 98.841 99.790 101.010 52.75 92.317 92.15295.282 42.2 95.103 95.805 95.939 21.1 91.876 91.968 93.847 10.55 94.98993.522 97.826 5.275 94.586 95.232 90.611 105.5 Epidermal sheet + 83.83384.515 84.903 84.4 placebo 95.620 96.033 98.178 52.75 85.635 88.16986.906 42.2 93.077 92.904 95.095 21.1 101.831 105.389 105.213 10.5584.046 85.095 89.945 5.275 88.881 86.540 86.828 105.5 Epidermal sheet90.465 92.089 91.501 84.4 81.350 82.276 82.694 52.75 87.669 89.09690.943 42.2 85.716 86.340 89.641 21.1 95.828 97.098 97.470 10.55 93.18094.971 97.099 5.275 88.938 91.447 85.995Tables 36-40, Statistical Analysis for Amount of Imiquimod that isRecovered Following Mass Balance Test

ANOVA statistical analysis (95% confidence level): Amount of imiquimodthat is recovered following mass balance test from receiver fluid (fromresults that are presented in FIG. 5) is shown in Table 36:

TABLE 36 Source DF SS MS F P Cl 14 0.12075 0.01006 1.84 0.066 Error 520.28455 0.00547 Total 64 0.40530 S = 0.07397 R-Sq = 29.79% R-Sq (adj) =13.59% Individual 95% CIs For Mean Based on Pooled StDev Level N MeanSt. Dev ----------+----------+----------+----------+ 3M Aldara ® 5% 40.05250 0.05909   (----------*----------) Imiquimod Cream 110 2.5% 60.00000 0.00000 (----------*----------) 250 2.5% 5 0.00400 0.00894(----------*----------) 182 3.75% 6 0.07833 0.14400    (----------*----------) 195 3.75% 4 0.08250 0.14500   (----------*----------) 123 2.5% 5 0.01200 0.01095(----------*----------) 125 2.5% 6 0.02333 0.02503 (----------*----------) 256 3.75% 5 0.15600 0.14064         (----------*----------) 197 3.75% 5 0.05800 0.06611  (----------*----------) 183 3.75% 4 0.01750 0.01708(----------*----------) 126 5 0.00600 0.00894 (----------*----------)Graceway Aldara ® 6 0.02833 0.03312  (----------*----------) 5%Imiquimod Cream 257 (1%) 4 0.00500 0.00577 (----------*----------)----------+----------+----------+----------+      0.000    0.080   0.160   0.240 Pooled StDev = 0.07397

ANOVA statistical analysis (95% confidence level): Amount of imiquimodthat is recovered following mass balance test from unabsorbed dose (fromresults that are presented in FIG. 5) is shown in Table 37:

TABLE 37 Source DF SS MS F P Cl 12 50777 4231 16.85 0.000 Error 52 13071251 Total 64 63848 S = 15.85 R-Sq = 79.53% R-Sq (adj) = 74.80%Individual 95% CIs For Mean Based on Pooled StDev Level N Mean St. Dev------------+------------+------------+------------+---- 3M Aldara ® 5%4 132.75 35.25                     (---*---) Imiquimod Cream 110 2.5% 652.93 9.69     (---*---) 250 2.5% 5 82.46 6.57        (---*---) 1823.75% 6 85.75 9.63         (---*---) 195 3.75% 4 74.19 13.80       (---*---) 123 2.5% 5 68.33 7.10        (---*---) 125 2.5% 6 72.829.61         (---*---) 256 3.75% 5 71.73 16.15        (---*---) 1973.75% 5 110.54 13.91         (---*---) 183 3.75% 4 113.85 23.27         (---*---) 126 5 63.98 11.78     (---*---) Graceway Aldara ® 6127.06 23.46            (---*---) 5% Imiquimod Cream 257 (1%) 4 28.889.20 (---*---) ------------+------------+------------+------------+---        35        70       105       140 Pooled StDev = 15.85

ANOVA statistical analysis (95% confidence level): Amount of imiquimodthat is recovered following mass balance test from Stratum corneum (fromresults that are presented in FIG. 5) is shown in Table 38:

TABLE 38 Source DF SS MS F P Cl 12 21479 1790 6.72 0.000 Error 52 13848266 Total 64 35327 S = 16.32 R-Sq = 60.80% R-Sq (adj) = 51.75%Individual 95% CIs For Mean Based on Pooled StDev Level N Mean St. Dev--+--------------+----------------+----------------+---------- 3MAldara ® 5% 4 74.38 21.17                (-----*-----) Imiquimod Cream110 2.5% 6 33.96 8.41     (----*----) 250 2.5% 5 28.30 8.21  (------*-----) 182 3.75% 6 46.85 13.50      (------*-----) 195 3.75% 457.41 22.92       (------*-----) 123 2.5% 5 35.93 23.25    (------*-----) 125 2.5% 6 28.88 10.80   (------*-----) 256 3.75% 533.41 10.67    (------*-----) 197 3.75% 5 41.61 14.62     (------*-----) 183 3.75% 4 41.00 13.97   (------*-----) 126 5 29.5911.11              (------*-----) Graceway Aldara ® 6 80.78 28.60 5%Imiquimod Cream 257 (1%) 4 12.49 7.49 (------*-----)--+--------------+----------------+----------------+----------   0        25          50           75 Pooled StDev = 16.32

ANOVA statistical analysis (95% confidence level): Amount of imiquimodthat is recovered following mass balance test from epidermis (fromresults that are presented in FIG. 5) is shown in Table 39:

TABLE 39 Source DF SS MS F P Cl 12 187.78 15.65 3.26 0.002 Error 52249.79 4.80 Total 64 437.57 S = 2.192 R-Sq = 42.91% R-Sq (adj) = 29.74%Individual 95% CIs For Mean Based on Pooled StDev Level N Mean St. Dev--------+----------+------------+------------+--- 3M Aldara ® 5% 4 6.6003.823                   (------*-----) Imiquimod Cream 110 2.5% 6 3.2481.717           (------*------) 250 2.5% 5 2.350 1.514      (------*------) 182 3.75% 6 3.643 2.083           (------*------)195 3.75% 4 7.055 4.580                   (------*------) 123 2.5% 54.196 3.782             (------*-----) 125 2.5% 6 1.123 1.039     (------*-----) 256 3.75% 5 1.990 1.588       (------*-----) 1973.75% 5 2.208 0.797        (------*-----) 183 3.75% 4 3.260 1.053       (------*-----) 126 5 2.360 0.903       (------*-----) GracewayAldara ® 6 2.895 1.752  (------*------) 5% Imiquimod Cream 257 (1%) 40.415 0.273 (------*-----)--------+----------+------------+------------+---      0.0     3.0      6.0       9.0 Pooled StDev = 2.192

ANOVA statistical analysis (95% confidence level): Amount of imiquimodthat is recovered following mass balance test from dermis (from resultsthat are presented in FIG. 5) is shown in Table 40:

TABLE 40 Source DF SS MS F P Cl 12 340.72 28.39 3.29 0.001 Error 52448.34 8.62 Total 64 789.06 S = 2.936 R-Sq = 43.18% R-Sq (adj) = 30.07%Individual 95% CIs For Mean Based on Pooled StDev Level N Mean St. Dev--------+-----------+--------------+--------------+--- 3M Aldara ® 5% 43.960 0.825        (--------*-------) Imiquimod Cream 110 2.5% 6 3.3231.068       (------*------) 250 2.5% 5 1.164 0.663 (--------*-------)182 3.75% 6 6.937 5.445                 (------*------) 195 3.75% 42.473 1.733         (--------*-------) 123 2.5% 5 1.796 0.715      (--------*-------) 125 2.5% 6 1.518 1.020      (--------*-------)256 3.75% 5 9.030 5.305                   (------*------) 197 3.75% 52.532 2.036        (--------*-------) 183 3.75% 4 5.110 4.638             (--------*-------) 126 5 4.436 3.626           (-------*------) Graceway Aldara ® 6 2.758 1.721         (------*------) 5% Imiquimod Cream 257 (1%) 4 1.533 2.099(--------*------) --------+-----------+--------------+--------------+---     0.0      3.5         7.0        10.5 Pooled StDev = 2.936

The results that are presented in FIG. 6, indicate that the delivery ofthe imiquimod into the receiver fluid, epidermis and dermis combinedfrom formulations 182, 195 and 256 are similar to the Aldara® 5%imiquimod cream formulation when comparing averages. With respect to thestatistical analysis, there is no statistical difference (p>0.05)between 110 (2.5%), 126 (2.5%), 123 (2.5%), 182, (3.75%), 195 (3.75%),256 (3.75%), 197 (3.75%) and 183 (3.75%) when compared to Aldara® 5%imiquimod cream formulation in the amount of imiquimod that is recoveredfrom the receiver fluid, epidermis and dermis combined.

In Table 41, ANOVA statistical analysis (95% confidence level) arepresented: Total amount of imiquimod that is recovered for eachformulation in the receiver fluid, epidermis and dermis combined (fromthe results that are presented in FIG. 6:

TABLE 41 Source DF SS MS F P Cl 12 340.72 28.39 3.29 0.001 Error 52448.34 8.62 Total 64 789.06 S = 3.819 R-Sq = 43.05% R-Sq (adj) = 29.91%Individual 95% CIs For Mean Based on Pooled StDev Level N Mean St. Dev----+---------+---------+---------+---- 257 (1%) 4 1.958 2.357(------*------) 110 2.5% 6 5.572 2.706      (------*------) 250 2.5% 53.524 1.445    (------*--------) 123 2.5% 5 6.010 4.296        (------*------) 125 2.5% 6 2.663 0.837 (---------*-------) 1262.5% 5 6.804 3.538        (---------*-------) 182 3.75% 6 10.662 6.441               (------*------) 195 3.75% 4 9.608 5.392           (--------*------) 256 3.75% 5 11.180 5.770             (------*------) 197 3.75% 5 4.800 1.749    (------*------)183 3.75% 4 8.388 3.666          (--------*--------) Individual 95% CIsFor Mean Based on Pooled StDev Level N Mean St. Dev----+---------+---------+---------+---- Graceway Aldara ® 6 5.682 2.671      (--------*--------) 5% Imiquimod Cream 257 (1%) 4 10.613 4.211             (---------*---------)----+----------+---------+---------+-----   0.0     5.0      10.0   15.0 Pooled StDev = 3.819

The results that are presented in FIG. 7 and statistical analysis inTables 42-46 indicate that there is a distinct dose proportionate trendbetween the amount of imiquimod that is recovered from each of thematrices with respect to the concentration of imiquimod in theformulation for both unabsorbed and Stratum corneum. The trend in thisdata, is also observed for the epidermis (with respect to average valuesin the statistical analysis).

In Tables 42-46, statistical analysis for the total amount of imiquimodrecovered from each of the matrices (1%, 2.5%, 3.75% and 5% w/wformulations)

ANOVA statistical analysis (95% confidence level): Total amount ofimiquimod that is recovered for imiquimod concentration combined fromeach of the matrices from unabsorbed dose (from results presented inFIG. 7) in Table 42:

TABLE 42 Source DF SS MS F P Cl 3 44198 14733 35.53 0.000 Error 61 25293415 Total 64 69491 S = 20.36 R-Sq = 63.60% R-Sq (adj) = 61.81%Individual 95% CIs For Mean Based on Pooled StDev Level N Mean St. Dev----------------+------------+------------+----------- +-   1% 4 28.889.20 (-------*-------)  2.5% 27 64.08 16.24              (-*--) 3.75% 2490.75 22.48                     (-*-)   5% 10 129.33 26.99                            (---*---)---------------+-------------+------------+----------+-           35       70       105      140 Pooled StDev = 20.36

ANOVA statistical analysis (95% confidence level): Total amount ofimiquimod that is recovered, for imiquimod concentration combined fromeach of the matrices from Strateum corneum (from results presented inFIG. 7) in Table 43:

TABLE 43 Source DF SS MS F P Cl 3 19744 6581 25.76 0.000 Error 61 15583255 Total 64 35327 S = 15.98 R-Sq = 55.89% R-Sq (adj) = 53.72%Individual 95% CIs For Mean Based on Pooled StDev Level N Mean St. Dev-+----------------+------------+---------------+-------   1% 4 12.497.49 (------*------)  2.5% 27 31.34 12.57           (--*-) 3.75% 2443.74 15.85               (-*--)   5% 10 78.79 24.79                              (---*---)-+---------------+-------------+------------+-----------  0          25       50        75 Pooled StDev = 15.98

ANOVA statistical analysis (95% confidence level): Total amount ofimiquimod that is recovered for imiquimod concentration combined fromeach of the matrices from epidermis (from results presented in FIG. 7)in Table 44:

TABLE 44 Source DF SS MS F P Cl 3 55.25 18.42 2.97 0.040 Error 61 382.326.27 Total 64 437.57 S = 2.504 R-Sq = 12.63% R-Sq (adj) = 8.33%Individual 95% CIs For Mean Based on Pooled StDev Level N Mean St. Dev------------+-----------+----------+---------+-   1% 4 0.415 0.273(-------------*------------)  2.5% 27 2.621 2.137               (--*---)3.75% 24 3.505 2.729                 (---*---)   5% 10 4.37 3.200                  (-----*-----)------------+-----------+----------+---------+-        0.0       2.5     5.0     7.5 Pooled StDev = 2.504

ANOVA statistical analysis (95% confidence level): Total amount ofimiquimod that is recovered for imiquimod concentration combined fromeach of the matrices from dermis (from results presented in FIG. 7) inTable 45:

TABLE 45 Source DF SS MS F P Cl 3 147.4 49.1 4.67 0.005 Error 61 641.710.5 Total 64 789.1 S = 3.243 R-Sq = 18.68% R-Sq (adj) = 14.68%Individual 95% CIs For Mean Based on Pooled StDev Level N Mean St. Dev---------+------------+------------+------------+--   1% 4 1.533 2.099(----------------*-------------------)  2.5% 27 2.223 1.974          (----*----) 3.75% 24 5.407 4.694                    (-----*----)   5% 10 3.239 1.502           (-------*-------)---------+------------+-----------+------------+--       0.0       2.5     5.0       7.5 Pooled StDev = 3.243

ANOVA statistical analysis (95% confidence level): Total amount ofimiquimod that is recovered for imiquimod concentration combined fromeach of the matrices from receiver fluid (from results presented in FIG.7) in Table 46:

TABLE 46 Source DF SS MS F P Cl 3 0.07047 0.02349 4.28 0.008 Error 616.33483 0.00549 Total 64 0.40530 S = 0.07409 R-Sq = 17.39% R-Sq (adj) =13.32% Individual 95% CIs For Mean Based on Pooled StDev Level N MeanSt. Dev ----+---------+---------+---------+-----   1% 4 0.00577 0.00577(-----------------*------------------)  2.5% 27 0.00926 0.01542        (-----*-----) 3.75% 24 0.08083 0.11632                      (-----*-----)   5% 10 0.03800 0.04392            (---------*---------)-----+------------+------------+-----------+----  −0.050     0.000    0.050     0.100 Pooled StDev = 0.07409

The following Tables 47-59 summarize results for formulations 126, 182and Pbo4.

TABLE 47 Stability of Imiquimod in the Formulations. Percentage ofimiquimod that is recovered from each formulation compared totheoretical when stored at 25° C. and 40° C. over a 6 month period. t =1 month 2 months t = 3 months t = 6 months Formulations t = 0 h 25° C.40° C. 25° C. 40° C. 25° C. 40° C. 25° C. 40° C. 182  96.76 ± 025 102.01± 0.01  98.46 ± 0.15  99.00 ± 0.12  98.07 ± 0.10 101.48 ± 0.27 104.39 ±1.55 102.91 ± 1.16  99.12 ± 0.45 PBO4 0 0 0 0 0 0 0 0 0 126 102.37 ±0.58 102.84 ± 0.45 204.11 ± 0.04 100.02 ± 0.95 101.32 ± 040  99.28 ±3.25  98.43 ± 0.55 101.95 ± 037 103.02 ± 1.89

TABLE 48 Stability of Imiquimod in the Formulations. Identification ofImiquimod when the formulations are stored at 25° C. and 40° C. over a 6month period (confirmed by HPLC). T = 1 month T = 2 months T = 3 monthsT = 6 months Formulations T = 0 25° C. 40° C. 25° C. 25° C. 40° C. 40°C. 25° C. 40° C. 182 Complies Complies Complies Complies CompileComplies Complie Comp les Complie 126 Complies Complies CompliesComplies Complie Complies Complie Complies Complie GWO3OP CompliesComplies Complies Complies Complie Complies Complie Complies Complie

TABLE 49 Stability of Benzyl Alcohol in the Formulations. Amount ofbenzyl alcohol that is recovered from each of the formulations when theformulations are stored at 25° C. and 40° C. over a 6 month period. t =1 month 2 months t = 3 months t = 6 months Formulations t = 0 h 25° C.40° C. 25° C. 40° C. 25° C. 40° C. 25° C. 40° C. 182 2.07 ± 0.00 2.17 ±0.00 1.95 ± 0.01 2.11 ± 0.04 1.97 ± 0.00 1.94 ± 1.82 ± 0.04 1.85 ± 0.031.48 ± 0.05 PB04 1.93 ± 0.02 1.83 ± 0.06 1.90 ± 0.03 1.91 ± 0.03 1.53 ±0.00 1.81 ± 1.39 ± 0.01 1.71 ± 0.01 1.08 ± 0.02 126 2.00 ± 0.02 2.02 ±0.01 1.89 ± 0.01 1.86 ± 0.02 1.65 ± 0.02 2.00 ± 1.70 ± 0.04 2.01 ± 0.031.55 ± 0.02

TABLE 50 Stability of Benzyl Alcohol in the Formulations. Identificationof Benzyl alcohol when the formulations are stored at 25° C. and 40° C.over a 6 month period (confirmed by HPLC. T = 1 month T = 2 months T = 3months T = 6 months Formulations T = 0 25° C. 40° C. 25° C. 25° C. 40°C. 40° C. 25° C. 40° C. 182 Complies Complies Complies Complies CompileComplies Complie Compiles Complie 126 Complies Complies CompliesComplies Complie Complies Complie Complies Complie PB04 CompliesComplies Complies Complies Complie Complies Complie Complies Complie

TABLE 51 Stability of Methylparabens in the Formulations. Amount ofMethylparabens that are recovered from each of the formulations when theformulations are stored at 25° C. and 40° C. over a 6 month period. t =1 month t = 2 months t = 3 months t = 6 months Formulations t = 0 h 25°C. 40° C. 25° C. 40° C. 25° C. 40° C. 25° C. 40° C. 182 0.18 ± 0.18 ±0.19 ± 020 ± 0.20 ± 0.19 ± 0.20 ± 0.19 ± 0.19 ± 0.001 0.000 0.001 0.0010.000 0.000 0.004 0.002 0.001 PB04 0.19 ± 0.19 ± 0.18 ± 0.20 ± 0.20 ±0.20 ± 0.20 ± 0.20 ± 0.20 ± 0.00 0.003 0.002 0.001 0.000 0.001 0.0010.001 0.002 126 0.20 ± 0.20 ± 0.19 ± 0.19 ± 0.21 ± 0.21 ± 0.20 ± 0.20 ±0.20 ± 0.002 0.001 0.000 0.001 0.00 0.001 0.001 0.001 0.001

TABLE 52 Stability of Methylparabens in the Formulations. Identificationof Methylparabens when the formulations are stored at 25° C. and 40° C.over a 6 month period (confirmed by HPLC). T = 1 month T = 2 months T =3 months T = 6 months Formulation T = 0 25° C. 40° C. 25° C. 25° C. 40°C. 40° C. 25° C. 40° C. 182 Complies Complies Complies Complies CompliesComplies Complies Complies Complies 126 Complies Complies CompliesComplies Complies Complies Complies Complies Complies PB04 CompliesComplies Complies Complies Complies Complies Complies Complies Complies

TABLE 53 Stability of Propylparabens in the Formulations. Amount ofPropylparabens that are recovered from each of the formulations when theformulations are stored at 25° C. and 40° C. over a 6 month period. t =1 month t = 2 months t = 3 months t = 6 months Formulations t = 0 h 25°C. 40° C. 25° C. 40° C. 25° C. 40° C. 25° C. 40° C. 182 0.019 ± 0.020 ±0.018 ± 0.018 ± 0.018 ± 0.021 ± 0.022 ± 0.019 ± 0.019 ± 0.000 0.0010.000 0.000 0.000 0.002 0.001 0.000 0.0010 PB04 0.018 ± 0.018 ± 0.16 ±0.19 ± 0.020 ± 0.020 ± 0.020 ± 0.018 ± 0.020 ± 0.001 0.001 0.001 0.0000.000 0.002 0.002 0.000 0.001 126 0.018 ± 0.019 ± 0.021 ± 0.018 ± 0.019± 0.020 ± 0.010 ± 0.020 ± 0.020 ± 0.000 0.001 0.001 0.000 0.001 0.0010.001 0.000 0.001

TABLE 54 Stability of Propylparabens in the Formulations. Identificationof Propylparabens when the formulations are stored at 25° C. and 40° C.over a 6 month period (confirmed by HPLC). T = 1 month T = 2 months T =3 months T = 6 months Formulation T = 0 25° C. 40° C. 25° C. 25° C. 40°C. 40° C. 25° C. 40° C. 182 Complies Complies Complies Complies CompliesComplies Complies Complies Complies 126 Complies Complies CompliesComplies Complies Complies Complies Complies Complies PB04 CompliesComplies Complies Complies Complies Complies Complies Complies Complies

TABLE 55 Microscopic Stability of the Formulations. The results of theparticle size for each formulation which is determined by opticalmicroscopy at 25° C. over a 6 month period. Particle size (μM) t = 1 t =2 t = 3 t = 6 Formulation t = 0 Month Months Months Months 182 <10 <10<10 <10 <10 PBO4 <10 <10 <10 <10 <10 126 <10 <10 <10 <10 <10

TABLE 56 pH stability of the Formulations. The results of the pH testfor each of the formulations when the formulations are stored at 25° C.and 40° C. over a 6 month period. Grey area indicate no test wasperformed. pH t=0 t = 1 month t = 2 months t = 3 months t = 6 monthsFormulation 25° C. 25° C. 40° C. 25° C. 40° C. 25° C. 40° C. 25° C. 40°C. 182 4.5 4.5 4.5 4.5 4.5 4.6 4.3 4.3 PBO4 4.5 4.2 4.5 4.2 4.2 4.1 4.14.0 4.0 126 4.2 4.3 4.3 4.3 4.3 4.3 4.3 4.1 4.1

TABLE 57 Macroscopic stability of the Formulations. The results of themacroscopic appearance test when the formulations are stored at 25° C.over a 6 month period. Appearance spatula Test (25° C. sample only)Visual Viscosity (25° C. sample only) 1 = 1 t = 2 t = 3 1 = 6 t = 1 t =2 t = t = 6 Formulation t = 0 month months months months t = 0 monthmonths months months 182 Very Very Very Very Very High Medium- Medium-Medium- High glossy glossy and glossy and glossy and glossy and HighHigh High and smooth smooth smooth smooth smooth 126 Glossy, Smooth,Glassy Slightly Glossy Medium Medium Medium Medium Low very slightly andtextured, viscosity slightly textured, smooth sheen textured glossy PB04Glossy Glossy Glossy Glossy Smooth Medium- Medium Medium- Low Low andand and and cream Low Low smooth smooth smooth smooth high sheen

TABLE 58 Brookfield and Bohlin Viscosity. The results of the viscosityand rheology measurements for the formulations that are stored at 25° C.over a 6 month period. Bohlin Viscosity (cps) Crossover Brookfield (cPs)(based on 3M method) Formulation G*(Pa) (o*) t = 1 t = 2 t = 3 t = 6 t =1 t = 2 t = 3 t = 6 Identity t = 0 t = 0 t = 0 Month Months MonthsMonths t = 0 Month Months Months Months 182 702 8.5 693067 1097000904667 523033 273233 18050 17850 18550 16820 13691 126 ** ** 430100235066 228104 212500 105720 16783 12739 14749 108565 87895 PB04 ** **227800 * * * * 10350 7953 5511 3550 2247 *Results not presented as thetorque is out of range (due to low viscosity) for the Brookfieldsviscometer based on the setting and spindle that are used for all theother samples. Alternative spindles and settings are investigated;however, the results are vastly different compared to previous readings.**no recorded measurements.

TABLE 59 Identification of 4-hydroxy Imiquimod when the formulations arestored at 25° C. and 40° C. over a 6 month period (confirmed by HPLC at318 nm). t = 0 t = 1 month t = 2 months T = 3 months t = 6 monthsFormulations 25° C. 25° C. 40° C. 25° C. 40° C. 25° C. 40° C. 25° C. 40°C. 182 NMT 0.1% NMT 0.1% NMT 0.1% NMT 0.1% NMT 0.1% NMT 0.1% NMT 0.1%NMT 0.1% NMT 0.1% w/w w/w w/w w/w w/w w/w w/w w/w w/w PBO4 NMT 0.1% NMT0.1% NMT 0.1% NMT 0.1% NMT 0.1% NMT 0.1% NMT 0.1% NMT 0.1% NMT 0.1% w/ww/w w/w w/w w/w w/w w/w w/w w/w 126 NMT 0.1% NMT 0.1% NMT 0.1% NMT 0.1%NMT 0.1% NMT 0.1% NMT 0.1% NMT 0.1% NMT 0.1% w/w w/w w/w w/w w/w w/w w/ww/w w/w

Example 24

Two Phase 3, Randomized, Double-Blind, Placebo-Controlled, Multi-Center,Efficacy and Safety Studies of 2.5% and 3.75% Imiquimod Creams in theTreatment of External Genital Warts

This Example 24 will study a shorter duration treatment regimenutilizing lower concentrations of imiquimod to allow for more frequentdosing. The lower concentrations of imiquimod should permit daily dosingsuch that the overall short treatment regimen (up to 8 weeks oftreatment) could still provide adequate clearing of externalgenital/perianal warts.

The clinical development program for the formulations of lower strengthsof imiquimod will investigate a patient population similar to thatevaluated in the development program for Aldara®. In addition to lowerstrengths, the key modification is to the treatment regimen itself, asthe treatment with the 2.5% and 3.75% imiquimod creams will be oncedaily for a maximum of 8 weeks, rather than the currently approvedregimen of 3 times per week with Aldara for up to 16 weeks. Eachstrength will be evaluated vs. placebo to determine the benefit riskprofile with each of these treatment regimen.

Study Objective

The primary objective of this Example is to compare the efficacy andsafety of 2.5% imiquimod cream and 3.75% imiquimod cream to placebocream, applied once daily for up to 8 weeks, in the treatment ofexternal genital warts (EGW).

The secondary objective of this study is to provide information onrecurrence of EGW.

Description of Study

This is a randomized, double-blind, placebo-controlled, multicenterPhase 3 study of 2.5% and 3.75% imiquimod creams in the treatment ofEGW. Two investigational treatments will be studied: 2.5% imiquimodcream once-a-day application for a maximum of 8 weeks and 3.75%imiquimod cream once-a-day for a maximum of 8 weeks. The study willconsist of a Screening visit and an Evaluation Period including amaximum 8-week Treatment Period and a maximum 8-week No-treatmentPeriod. Subjects with complete clearance at the end of study (EOS) willbe followed for a maximum of 12 weeks for recurrence. During theEvaluation Period, subjects will be followed until they have achievedcomplete clearance of all warts. Any subject determined to have achievedcomplete wart clearance at any time through the Week 16 visit will enterthe maximum 12-week Follow-up Period for evaluation of recurrence. Thetotal study duration is a maximum of 28 weeks from randomization.

Approximately 450 subjects with at least 2 and up to 30 externalgenital/perianal warts will be randomized. Subjects will be screened forstudy eligibility during the 4 weeks prior to randomization. During theScreening Period, the medical history, including genital/perianal warthistory and wart treatment history, and demographic information,including sex, age, and race will be recorded. In addition, a physicalexamination, including vital signs and clinical safety laboratory tests,will be performed for each subject. If clinically indicated, a sexuallytransmitted diseases (STD) screen may be performed. Subjects with apositive screen for STD may participate in the study if they otherwisemeet the required Inclusion/Exclusion Criteria. For female subjects, apelvic exam/Pap smear will be performed unless a normal (negative) Papsmear result is available and was performed within 6 months ofenrollment.

Qualified subjects will be randomized to receive one of 3 treatments:2.5% imiquimod cream, 3.75% imiquimod cream, or placebo cream. Subjectswill apply study cream once daily for a maximum of 8 weeks. Subjectswill be stratified by gender and will be randomized to treatment with anallocation ratio of 2:2:1 in favor of the active treatments. Allsubjects will be seen every 2 weeks for up to 16 weeks, depending oncomplete clearance of all baseline and new warts.

In the Evaluation Period, subjects will apply investigative cream to theidentified treatment area for a maximum of 8 weeks. If the subject hasnot achieved complete wart clearance by the Week 8 visit (end oftreatment, EOT), the subject will be followed for an additional maximumof 8 weeks. Subjects determined to have achieved clearance of all wartsat any time through Week 16 will complete procedures for the EOS visitand will immediately enter the Follow-up Period for determination ofrecurrence. In the Follow-up Period, subjects will be followed every 4weeks for up to 12 weeks or until the recurrence of warts. The 2.5% and3.75% imiquimod creams that will be used this Example 24 have the sameformulations as the 2.5% and 3.75% imiquimod creams that were used inthe EGWs studies reported in Examples 23-26, which are described inapplication for U.S. patent, Ser. No. 12/636,613 filed Dec. 11, 2009,which is incorporated herein by reference in its entirety.

Clinical evaluations, including count of warts and assessment of localskin reactions, and recording of adverse events (AEs) and concomitantmedications will be performed. Safety laboratory tests will also beperformed prior to treatment and at the EOS visit.

Study Number: GW01-0805

of 2.5% imiquimod cream and 3.75% imiquimod cream with that of placebocream, applied once daily for up to 8 weeks, in the treatment of EGW.The secondary objective of this study was to provide information on therecurrence of EGW.

Methodology: This was a randomized, double-blind, placebo-controlled,multicenter study that compared the efficacy and safety of 2.5%imiquimod cream and 3.75% imiquimod cream with that of placebo in thetreatment of EGW. The study consisted of a screening visit and anevaluation period that included a maximum 8-week treatment period and amaximum 8-week no-treatment period. Subjects who achieved completeclearance at End of Study (EOS) entered a maximum 12-week follow-upperiod for evaluation of recurrence. The total study duration was amaximum of 28 weeks from randomization.

Subjects determined to be eligible during the screening period werestratified by gender and randomized in a 2:2:1 ratio to 2.5% imiquimodcream, 3.75% imiquimod cream, or placebo cream. Subjects were scheduledfor 1 prestudy screening visit, and then were scheduled for visits every2 weeks for up to 16 weeks during the evaluation period, depending oncomplete clearance of all baseline and new warts. During the evaluationperiod, subjects applied investigative cream to the identified treatmentarea for a maximum of 8 weeks. If the subject did not achieve completewart clearance by the Week 8 visit (End of Treatment, EOT), the subjectwas monitored for an additional maximum of 8 weeks. Subjects determinedto have achieved clearance of all warts at any time through Week 16completed procedures for the EOS visit and were eligible to immediatelyenter the follow-up period for determination of recurrence. During thefollow-up period, subjects were monitored every 4 weeks for up to 12weeks or until the recurrence of warts.

Clinical evaluations included counts of the number of warts, assessmentsof local skin reactions (LSRs), and recordings of adverse events (AEs)and concomitant medications. At selected centers, photography wasperformed at designated visits: Laboratory tests were also performedprior to treatment and at the EOS visit to assess safety.

The study design is presented schematically in Tables 60 and 61 below.

TABLE 60 Study Design-Evaluation Period Screening Treatment PeriodNo-treatment Period Week Week 0 Week 8/ Week Week Week Week 16/ −4 to 0Day 1 Week 2 Week 4 Week 6 EOT 10 12 14 EOS Visit 1 Visit 2 Visit 3Visit 4 Visit 5 Visit 6 Visit 7 Visit 8 Visit 9 Visit 10 Note: At anytime during the Evaluation Period (i.e., any time after Visit 2), asubject who achieved clearance of all warts concluded the evaluationperiod and was eligible to enter the Follow-up for Recurrence Period.

TABLE 61 Study Design—Follow-up for Recurrence Period Follow-up Period(Only in subjects with clearance of all warts) Week 4 Week 8 Week 12Post-EOS Post-EOS Post-EOS Follow-up Visit 1 Follow-up Visit 2 Follow-upVisit 3Discussion of Study Design, Including the Choice of Control Groups

This was a randomized, double-blind, placebo-controlled, multicenterstudy. In order to assess the effect of imiquimod in the treatment ofEGW, a placebo-control group was included in the study design. The studymedications were identical with the exception of the absence ofimiquimod in the placebo cream and the concentration of imiquimod (2.5%or 3.75%) in the active formulations.

The double-blind study design, in which the treatment assignment wasconcealed from the subjects, investigators, and all individuals involvedin study execution, monitoring, and data collection, was chosen toprovide an unbiased evaluation of the study medications. Comparison ofeach imiquimod group to the placebo group provides an unbiased test ofthe effect of imiquimod.

The 8-week treatment period was selected based on market experience ofthe use of Aldara to treat EGW, in which treatment duration greater than8 weeks appears to be rare. Subjects who did not experience clearanceduring the treatment period were observed for an additional no-treatmentperiod of up to 8 weeks. Once clearance was achieved at any time duringthe study, subjects were observed during a 12-week follow-up period todetermine if the EGW recurred.

Selection of Study Population

It was planned to enroll approximately 450 subjects in a 2:2:1 ratio:approximately 180 in each active-treatment group and 90 in the placebogroup. Forty-five investigative study centers in the United States (US)participated in the study, although 2 centers did not enroll anysubjects. Study centers could enroll a maximum of 30 subjects percenter. Enrollment was stopped at all centers when the study enrollmentgoal was reached.

Inclusion Criteria

Subjects could participate in the study if they met the followinginclusion criteria:

-   -   1. Were willing and able to give informed consent—for subjects        under 18, the parent/legal guardian was required to give written        informed consent and the subject was required to provide written        assent in accordance with local regulations;    -   2. Were at least 12 years of age at the time of initial        screening;    -   3. Were willing and able to participate in the study as        outpatients, making frequent visits to the study center during        the treatment and follow-up periods, and to comply with all        study requirements;    -   4. Had a diagnosis of external genital/perianal warts with at        least 2 warts and no more than 30 warts located in one or more        of the following anatomic locations:        -   In both sexes: inguinal, perineal, and perianal areas;        -   In men: over the glans penis, penis shaft, scrotum, and            foreskin;        -   In women: on the vulva;    -   5. Had total wart areas of at least 10 mm²;    -   6. Were judged to be in good health based upon the results of a        medical history, physical examination, and safety laboratory        profile;    -   7. If female and of childbearing potential, had a negative serum        pregnancy test at Screening and a negative urine pregnancy test        prior to randomization and were willing to use effective        contraception; and    -   8. If male or a male partner of a female subject, were willing        to use condoms for sexual activities during the study.        Exclusion Criteria

Subjects were excluded from the study if they met any of the followingcriteria:

-   1. Had received any topical and/or destructive treatments for    external genital warts within 4 weeks (within 12 months for    imiquimod, and within 12 weeks for sinecatechins) prior to    enrollment (i.e., the randomization visit);-   2. Had received any of the following treatments within the indicated    time intervals prior to enrollment:

Medication/Treatment Washout Any marketed or investigational HPVvaccines 12 months Imiquimod 12 months Sinecatechins (Veregen ®) 12weeks Interferon/Interferon inducer 4 weeks Cytotoxic drugs 4 weeksImmunomodulators or immunosuppressive therapies 4 weeks Oral antiviraldrugs (with the exception of oral 4 weeks acyclovir and acyclovirrelated drugs for suppressive or acute therapy herpes; or oseltamivirfor prophylaxis or acute therapy of influenza) Topical antiviral drugs(including topical acyclovir 4 weeks and acyclovir related drugs) in thewart areas Podophyllotoxin/Podofilox in the wart areas 4 weeks Oral andparenteral corticosteroids 4 weeks (inhaled/intranasal steroids arepermitted) Any topical prescription therapy for any conditions 4 weeksin the wart areas Dermatologic/cosmetic procedures or surgeries in the 4weeks wart areas

-   3. Had any evidence (physical or laboratory) of clinically    significant or unstable disease and/or any condition that might have    interfered with the response to the study treatment or altered the    natural history of EGW;-   4. Were currently participating in another clinical study or had    completed another clinical study with an investigational drug or    device within the past 4 weeks;-   5. Had known or active chemical dependency or alcoholism as assessed    by the investigator;-   6. Had known allergies to study drug or any excipient in the study    cream;-   7. Were currently immunosuppressed or had a history of    immunosuppression;-   8. Had a planned surgery that would cause an interruption of study    treatment;-   9. Had sexual partners currently in treatment with an approved or    investigational treatment for EGW;-   10. Had any current or recurrent malignancies in the genital or    treatment area;-   11. Had any untreated or unstable genital infections (other than    genital warts);-   12. Had any of the following conditions:    -   known human immunodeficiency virus (HIV) infection;    -   current or past history of high risk HPV infection (e.g., HPV        16, 18, etc);    -   an outbreak of herpes genitalis in the wart areas within 4 weeks        prior to enrollment;    -   internal (rectal, urethral, vaginal/cervical) warts that        required or were undergoing treatment;    -   a dermatological disease (e.g., psoriasis) or skin condition in        the wart areas which may have caused difficulty with        examination;-   13. If female, had clinically significant abnormalities on pelvic    examination or had laboratory test results showing high-grade    pathology (e.g., high-grade squamous intraepithelial lesion,    moderate or severe dysplasia, squamous cell carcinoma);-   14. If female, were nursing or pregnant or planned to become    pregnant during the study.    Removal of Patients from Therapy or Assessment

Subjects could withdraw from the study or be withdrawn by theinvestigator at any time without prejudice to their future medical care.Any subject who did not comply with the inclusion/exclusion criteriacould be withdrawn from further participation in the study.

Subjects could also be discontinued if the investigator determined thatLSRs or AEs were of such severe intensity, serious events, or of aduration sufficient to warrant discontinuation, or if a subject requiredtreatment for a suspected malignancy or other condition within thetreatment or surrounding area. If a subject discontinued due to an LSR,the LSR was recorded as an AE, and the subject was monitored until theAE resolved to the investigator's satisfaction.

Any subject who received study drug and discontinued prematurely fromthe study was to return to the study center for EOS procedures. Subjectswho discontinued prematurely from the study for any reasons were notreplaced.

Treatments Administered

The test products were 2.5% imiquimod cream and 3.75% imiquimod cream.The reference therapy was placebo cream. Subjects applied the study drugin a thin layer once daily to each wart identified at Baseline and anynew wart that appeared during the treatment period. A maximum of 1packet (250 mg) of study drug was applied for a given dose (250 mg of3.75% cream is equivalent to 9.375 mg imiquimod, and 250 mg of 2.5%cream is equivalent to 6.25 mg imiquimod). Study drug was applied priorto normal sleeping hours and removed approximately 8 hours later withmild soap and water. Subjects were to continue to apply study cream toall identified wart/wart areas until all warts were cleared.

The investigational products, 2.5% imiquimod cream and 3.75% imiquimodcream, contained imiquimod, isostearic acid, benzyl alcohol, cetylalcohol, stearyl alcohol, polysorbate 60, sorbitan monostearate, whitepetrolatum, glycerin, methyl paraben, propyl paraben, purified water,and xanthan gum. The placebo cream contained the same ingredients as theactive formulations with the exception of imiquimod.

Method of Assigning Patients to Treatment Groups

Subjects were randomly assigned to study treatments in a 2:2:1 ratio(2.5% imiquimod cream:3.75% imiquimod cream:placebo cream).

Selection of Doses in the Study

The approved dosing regimen for Aldara® (imiquimod) Cream, 5% for EGW is3 times per week until warts are cleared, up to 16 weeks of treatment.This protocol studied a treatment regimen shorter in duration, and usedlower concentrations of imiquimod to allow for more frequent dosing. Thelower concentrations of imiquimod used in this study were chosen topermit daily dosing such that the overall shortened treatment regimen (8weeks compared with a 16-week treatment regimen for Aldara) could stillprovide adequate clearing of EGW.

Selection and Timing of Dose for Each Patient

Subjects meeting all inclusion and no exclusion criteria were randomlyassigned in a 2:2:1 ratio to 1 of the 3 treatment groups (2.5% imiquimodcream:3.7% imiquimod cream:or placebo cream).

Each dose of study drug was to be applied by the subject atapproximately the same time of day. To reduce the risk of study drugremoval from daily hygienic or physical activities, study drug was to beapplied just prior to the subject's normal sleeping hours.

Subjects were to wash the treatment area with mild soap and water beforeapplying the study medication, allow the area to dry thoroughly, andthen apply the study medication once daily. Subjects were to apply athin layer of study cream to each wart identified at Baseline and anynew wart that appeared during the treatment period. Only up to onepacket of study cream was to be applied per application.

The subjects were encouraged to leave study cream on for approximately 8hours, preferably during normal sleeping hours, and were not to wash thetreatment area, swim, shower or bathe, or have sexual contacts while thestudy medication was on the skin. Subjects could wash the study creamoff with soap and water any time after approximately 8 hours ofapplication. Subjects were to continue applying the study cream for amaximum of 8 weeks or until the investigator determined that they hadachieved complete clearance of all (baseline and new) warts. Subjectswere not to make up any missed doses.

Rest periods, or temporary interruptions of dosing due to intolerablelocal skin reactions, were allowed during the study if the investigatoror subject (or legal parent or guardian) decided that study drugapplication should be interrupted. Subjects who were placed on a restperiod were to be seen by the investigator prior to resuming treatmentwith study drug in order to assess if the recovery of the treatment sitewas sufficient. Doses missed due to a rest period were not counted asmissed doses in the assessment of subject compliance with the treatmentregimen. The study visit schedule and procedures were not to be altereddue to missed doses or rest periods. If a subject experienced a stronglocal reaction in one treatment area but not in other treated areas, thesubject could temporarily stop applying study cream in that affectedarea while continuing study treatment in the other areas.

Treatment of New Warts

During treatment period, any new warts appearing in any of theprotocol-defined anatomic locations were treated with the study cream.Neither the warts present at Baseline nor new warts were allowed to betreated during the no-treatment period (i.e., from the Week 8/EOT visitto the Week 16 visit).

Blinding

This study was conducted as a double-blind study, i.e., the treatmentassignment was concealed from the subjects, the investigators and theirstaff, and the clinical research team.

Treatment supplies for each subject included treatment kits for 8 weeksof treatment. Each treatment kit contained 4 supply boxes of study creamand one emergency box, each box containing a 2-week supply of studycream. At the randomization/Day 1 visit, a randomization number wasassigned to each subject. Each subject was assigned the next availabletreatment kit number available at the site, starting from the lowestnumber for each gender and proceeding in numerical order to the highestnumber.

The randomization code for each subject could be accessed via thedouble-blind tear-off label, but was to be broken for an individualsubject only in an emergency situation such as a serious adverse event(SAE). The study monitor or project manager was to be informed prior toany emergency unblinding. If the code for a subject was broken, theinvestigator was to document promptly the premature unblinding of theinvestigational product in the electronic case report form (eCRF)system.

No premature unblinding was performed. The treatment assignments wereunblinded approximately 3 months after the last subject contact afterall data queries had been answered and the database had been locked.

Prior and Concomitant Therapy

At each visit, prior and concomitant medications and therapies werereviewed. The name of the medication (trade or generic name), indicationfor use, and start and stop dates were recorded for any medication used.

Restricted Medications/Treatments

The following medications, preparations, and treatments that couldpotentially affect the study results were prohibited during the study:

-   -   1. Imiquimod 5% cream (Aldara®);    -   2. Any marketed or investigational HPV vaccines;    -   3. Sinecatechins (Veregen);    -   4. Interferon or interferon inducers;    -   5. Cytotoxic drugs;    -   6. Immunomodulators or immunosuppressive therapies;    -   7. Oral or parenteral corticosteroids (inhaled/intranasal        steroids are permitted);    -   8. Oral antiviral drugs (with the exception of oral acyclovir        and acyclovir related drugs for suppressive or acute therapy        herpes; or oseltamivir for prophylaxis or acute therapy of        influenza);    -   9. Topical antiviral drugs (including topical acyclovir and        acyclovir related drugs) in the treatment areas;    -   10. Podophyllotoxin/Podofilox in the treatment areas;    -   11. Any topical prescription medications in the treatment areas;    -   12. Dermatologic/cosmetic procedures or surgeries in the        treatment areas.        Treatment Compliance

Study center personnel carefully queried each subject and reviewed thestudy diary at each treatment study visit to make sure the subject wasdosing with study drug as indicated. The numbers of returned used andunused study packets were counted and recorded, and any discrepancieswere discussed with the subject. During the treatment period, the studycenter personnel continued to instruct the subject on dosing proceduresuntil the subject demonstrated compliance with study drug application.If at any time the investigator felt that a subject had missed asignificant number of doses (exclusive of rest periods) or was notcompliant with the study requirements, the investigator was to contactthe project manager or study monitor to review the subject's compliancestatus and to determine a course of action.

Efficacy and Safety Variables

Efficacy and Safety Measurements Assessed

A schedule of study visits and procedures is presented in the Tablebelow. Source documentation was completed at each subject's visit, andthe data captured in the source documents was subsequently entered intoeCRFs by the investigator or designee. The evaluator who performed theEGW count and LSR assessment at Baseline was to perform theseassessments at the subsequent visits if possible.

Photographs were taken of the treatment area at selected centers, forinformational purposes only. Only subjects who had signed a photographicconsent form were to be photographed. No subjects under the age of 18years (19 in Nebraska, Alabama, Alaska, or Wyoming) were photographed.The majority of subjects who participated in this trial did not havephotographs of the treatment area taken. Cameras, detailed instructionson taking the photographs, and related items for photography wereprovided to the study centers by Canfield Scientific, Inc.

Criteria for Evaluation:

Efficacy Assessments

Count of External Genital/Perianal Warts (EGWS)

In order to qualify for this study, subjects had to have at least 2warts and no more than 30 warts in the genital/perianal area at thescreening and randomization/Day 1 visits. At each study visit includingScreening, the number of warts, including new warts, was documented onthe source documents and eCRF for each of the following anatomiclocations:

-   -   In both sexes: inguinal, perineal, and perianal areas;    -   In men: over the glans penis, penis shaft, scrotum, and foreskin        (if circumcised, the foreskin area was marked as “not        applicable”);    -   In women: on the vulva.

Any warts that were visible to the naked eye were included in the lesioncount as separate lesions.

In the event that the margins or boundaries of some warts could not bediscerned due to local skin reactions obscuring the field, the bestestimate by clinical assessment of the number of warts in each anatomiclocation was made and the count included.

If possible, the same investigator who counted the warts at Baselinecompleted wart counts at subsequent study visits.

Measurement of Baseline Wart Area

At the screening and randomization/Day 1 visits, the size of each wartor wart cluster was measured by length and width. The total wart areaswere to equal at least 10 mm² in order to qualify for this study. Theinvestigator measured the total baseline wart area to be treated in mm².The total baseline wart area was the sum of individual areas for eachwart or cluster of warts. It was preferred that each subject's wartareas be measured by the same investigator at both visits. If the wartareas were not continuous, the total areas were to be calculated andrecorded on the source documents and eCRF.

Treatment of New Warts

During the treatment period, any new warts that appeared in any of theprotocol defined anatomic locations were treated with study cream.Treatment for any warts, Baseline or new, was not allowed during theno-treatment period (i.e., from the EOT visit to the Week 16 visit).

Safety Assessments

Safety assessments included visual assessments of local skin reactions(LSRs) at each study visit after the screening visit, including anytemporary interruptions of dosing (i.e., rest periods) required inresponse to LSRs; all reports of AEs and SAEs, with their severity andrelationship to study drug; results of clinical laboratory tests(including urine pregnancy tests for women of childbearing potential);pelvic examinations with Pap smears in women; findings of a generalphysical examination at the screening visit, and intercurrentdermatologic conditions occurring within or outside of the treatmentarea.

Full information about the definition of AEs and SAEs, the procedure forreporting them, and the assessment of other safety parameters is givenin the protocol.

Adverse Events

Subjects were queried indirectly regarding AEs during each study visit.All AEs that occurred during the study period were recorded on theappropriate eCRF. The description of the AE included the dates of onsetand resolution (duration), severity, relationship to study treatment orother therapy, action taken (if any), and outcome. If the investigatorconsidered it necessary, he or she was to contact the sponsor withregard to any AE that occurred after a subject ended studyparticipation. Any treatment-related AEs or LSRs that were ongoing atthe end of the study were followed to the investigator's satisfaction.The study period for the purpose of AE reporting was defined as theperiod from the prestudy screening or the initiation of any studyprocedures to the end of the follow-up period.

An adverse event was defined as any untoward medical occurrence in apatient or clinical investigation subject that was temporally related toprotocol procedures, including the administration of a pharmaceuticalproduct at any dose, but that did not necessarily have a causalrelationship with the treatment. Laboratory values or results of otherdiagnostic procedures considered by the investigator to be clinicallysignificant were captured as AEs and summarized accordingly.

Local skin reactions were not recorded as AEs unless they extendedbeyond the anatomic treatment area, if they required any medicalinterventions, or if the LSR resulted in subject discontinuation fromthe study. Application site reactions other than those described as LSRs(eg, vesicles, burning, itching, bleeding, soreness, and induration)were recorded as AEs.

Severity:

Terms used to describe the severity of an AE were mild, moderate, andsevere. These terms were defined as follows:

-   -   Mild—The subject was aware of the signs and symptoms but the        signs and symptoms were easily tolerated.    -   Moderate—The signs and symptoms were sufficient to restrict, but        did not prevent, usual daily activity for the subject.    -   Severe—The subject was unable to perform usual daily activity.

Serious Adverse Events:

An SAE was any AE that, at any dose, resulted in any of the followingoutcomes: death, life-threatening AE, inpatient hospitalization orprolongation of existing hospitalization, persistent or significantdisability/incapacity, or a congenital anomaly/birth defect.

An event was considered serious when, based upon appropriate medicaljudgment, it jeopardized the subject and may have required medical orsurgical intervention to prevent one of the outcomes listed above.

A life-threatening AE was any AE that, at any dose, placed the subject,in the view of the investigator, at immediate risk of death from thereaction as it occurred. It did not include a reaction or event that,had it occurred in a more severe form, might have caused death.

Local Skin Reactions

Local skin reactions in the treatment and/or immediate surrounding areawere clinically identified by the following categories: erythema, edema,weeping/exudate, flaking/scaling/dryness, scabbing/crusting, anderosion/ulceration. At each study visit after the screening visit, theinvestigator visually assessed the treatment and immediate surroundingareas and graded the intensity of each LSR category using the scales inTables 62 and 63.

TABLE 62 Local Skin Reaction Scale Local Skin Severity DefinitionsReaction 0 1 (Mild) 2 (Moderate) 3 (Severe) Erythema None Faint to mildModerate Intense redness redness redness Edema None Mild visible orEasily palpable Gross barely palpable swelling/ swelling/ swelling/induration induration induration Weeping/ None Minimal Moderate Heavyexudate exudate exudate exudate Flaking/ None Mild Moderate Severescaling/ dryness/ dryness/ dryness/ dryness flaking flaking flakingScabbing/ None Crusting Serous scab Eschar crusting

TABLE 63 Local Skin Reaction Scale (erosion/ulceration) Local SkinSeverity Definitions Reactions 0 2 3 Erosion/ulceration None ErosionUlceration

Erosion/ulceration intensity was originally collected as 0 None,1=Erosion, and 2=Ulceration. For consistency in the analysis of LSRintensities and sum score, these were recoded as 0=None, 2=Erosion, and3=Ulceration.

Local skin reactions were assessed independently from AEs, and wererecorded as AEs only if they extended beyond the immediate surroundingarea, if they required any medical interventions, or if the LSR resultedin subject discontinuation from the study. Other application sitereactions not listed above (eg, vesicles, burning, itching, bleeding,soreness, and induration) were recorded as AEs.

Intercurrent Dermatological Conditions

Occurring Within the Treatment Area

-   -   Dermatological Conditions—Subjects who experienced        dermatological conditions within the treatment area that were        unrelated to or may have been exacerbated by study cream could        be discontinued from the study if these conditions impaired wart        count and LSR assessments. In such a circumstance, the EOS        procedures were to be completed.    -   Herpes Genitalis—A subject who had an outbreak of herpes        genitalis that required treatment during the study in the        genital wart areas could remain in the study but was to stop        dosing with study cream. If the outbreak of herpes was distal        from the wart areas and did not interfere with study drug        application or wart evaluation, the subject was to remain in the        study and could continue dosing with study cream. Subjects could        receive treatment for herpes genitalis with oral acyclovir,        famciclovir, and valaciclovir.

Occurring Outside the Treatment Area

-   -   Dermatological Conditions—Subjects who experienced        dermatological conditions outside the treatment area or area        immediately surrounding the treatment area could receive        treatments for these conditions with the exception of treatments        listed above.    -   Vaginal and/or Cervical Warts During the study, subjects who        developed vaginal and/or cervical warts were to be monitored by        the investigator throughout the. treatment period. These        diseases could be treated after the subject exited the study.    -   Vulvar Intraepithelial Neoplasia or Vaginal Intraepithelial        Neoplasia—If vulvar or vaginal intraepithelial neoplasia was        diagnosed during the study, the investigator was to consult with        the medical monitor regarding the subject's continued        participation in the study.    -   Rectal Mucosal or Urethral Warts—Rectal and urethral warts could        be treated with conventional therapy only after the subject        exited the study.        Rest Periods

A rest period was a temporary interruption of dosing due to intolerableLSRs. Doses that were missed due to a subject's noncompliance with thetreatment regimen were not considered a rest period. Rest periods fromdaily treatment were instituted by the investigator as needed, withresumption of treatment at the investigator's discretion.

Clinical Laboratory Tests

Laboratory Tests:

Subjects had samples taken at the prestudy screening visit and at theEOS visit for analysis of the following parameters:

-   -   Hematology: hemoglobin, hematocrit, red blood cell count (RBC),        white blood count (WBC) with differential, and platelet count;    -   Serum chemistry: glucose (non-fasting), blood urea nitrogen        (BUN), creatinine, cholesterol, total bilirubin, aspartate        aminotransferase (AST), alanine aminotransferase (ALT), lactate        dehydrogenase (LDH), alkaline phosphatase (AP), potassium,        sodium, calcium, chloride, total protein, albumin, and        phosphorous;    -   Serum pregnancy test: females of childbearing potential        underwent a serum pregnancy test at the screening visit, and the        test result had to be negative for the subject to participate in        the study;    -   Urinalysis: color/appearance, glucose, pH, ketones, specific        gravity, microscopic examination, and protein;

The samples were analyzed at a central laboratory, Covance CentralLaboratory Services, 8211 Scicor Drive, Indianapolis, Ind. 46214. Anylaboratory test result that the investigator considered to be clinicallysignificant was recorded as an AE.

Urine Pregnancy Tests: Females of childbearing potential underwent aurine pregnancy test (UPT) at Screening (in addition to a serumpregnancy test), the randomization/Day 1 visit, every 4 weeks during theevaluation period, and at the EOT visit. If either the UPT or the serumpregnancy test was positive prior to randomization, the subject was notpermitted to enroll in the study. Any subject who became pregnant duringtreatment was discontinued from further treatment. If there was asuspicion of pregnancy at any time during the treatment period, a urinesample was obtained and tested. All pregnancies were to be immediatelyreported to the medical monitor and followed through to resolution.Subjects were to continue with follow-up visits.

Sexually transmitted disease (STD) Screen: If applicable or ifclinically indicated, an STD screen was performed at the screeningvisit. This was not considered part of the protocol.

General Physical Examination

At the screening visit, the investigator completed a general physicalexamination that included measurement of blood pressure, pulse rate,temperature, weight, and respiration rate.

Pelvic Examination and PAP Smear

For female subjects, a pelvic examination including a Pap smear wasperformed at the screening visit unless a normal (negative) Pap smearresult was available and had been performed within 6 months ofenrollment. Subjects with Pap smear results which were negative (normal)could be enrolled. Subjects with atypical squamous cells of undeterminedsignificance (ASCUS) or low grade squamous intraepithelial lesion (LSIL)may have been eligible for enrollment if per usual clinical follow-upthere was no suspicion of high grade pathology. Subjects with resultsshowing high-grade pathology were not to be enrolled in the study andwere to be followed appropriately or referred to their primary carephysician for further care. The ThinPrep® Pap (ie, Papanicolaou) testwas the only test that was performed in this study. The samples wereanalyzed at a central laboratory, South Bend Medical Foundation, Inc.,530 N. Lafayette Blvd., South Bend, Ind. 46601. Subjects with a(negative/normal) Pap smear result obtained within 6 months prior toenrollment did not need to have the test repeated.

Appropriateness of Measurements

External genital warts are clinically diagnosed and treated in NorthAmerica and elsewhere. A count of the number of clinically visible EGWsby a qualified investigator is an appropriate measurement of theefficacy of a treatment for EGW. The safety assessments, which includedAE monitoring and clinical laboratory testing and which followedstandard medical practice guidelines, are accepted measures that providegeneral health assessments. Because imiquimod therapy has been known tobe associated with LSRs, the type and severity of these were monitoredseparately from other AEs. These measures are generally recognized asappropriate for the purposes of this study.

Efficacy Analyses

Primary Efficacy Variable

The primary efficacy variable was the subject status with respect tocomplete clearance of all warts (baseline and new) in all anatomic areasat EOS (Week 16), as determined by the investigator.

Secondary and Tertiary Efficacy Variables

Secondary efficacy variables were the following:

-   -   Subject status with respect to partial clearance of baseline        warts, defined as at least a 75% reduction in the number of        baseline warts, at EOS/Week 16.    -   Percent change from Baseline to EOS in the total number of        warts.    -   Subject status with respect to complete clearance of all warts        at EOS and remained cleared in all anatomic areas, as determined        by the investigator, through the end of the follow-up for        recurrence period.    -   Time from Baseline to complete clearance of all warts, as        determined by the investigator.

The tertiary efficacy variables are the following:

-   -   Subject status with respect to complete clearance of all warts        (baseline and new) in all anatomic areas, at EOT/Week 8.    -   Subject status with respect to at least a 50% reduction in the        number of baseline warts at EOS/Week 16.        Statistical Methods for Efficacy Analyses

Efficacy analyses were conducted on the ITT population and on the PPpopulation. For the primary efficacy variable, imputations were made formissing data points using last observation carried forward (LOCF,primary analysis), taking all missed observations as failure(sensitivity analysis), and using observed cases (supportive analysis).For the ITT population, subjects who had no post-baseline data wereincluded in the analysis carrying forward the baseline data. The PPpopulation analysis used observed cases, except for complete clearanceand for recurrence.

Analysis of the Primary Efficacy Variable

The primary efficacy endpoint, complete clearance rate at the EOS, wasanalyzed using Cochran-Mantel-Haenszel (CMH) statistics, stratifying bygender and site. All pairwise comparisons of active treatment versusplacebo were made using Hochberg's modified Bonferroni procedure. Ifeither test was significant at a 0.025 level of significance, then thattest was considered significant. Otherwise, if both tests weresignificant at 0.05, then both tests were considered significant. The3.75% and 2.5% treatment groups were compared to each other at the 0.05level of significance if at least one of these treatment groups wasfound to be different than the placebo using the Hochberg's test.

In the primary analysis of complete clearance rate, the Breslow-Daystatistic was tested at the 10% level for heterogeneity of the oddsratios across analysis sites. A finding of statistical significance inthis test was followed by exploratory analyses to characterize thesource of the heterogeneity.

Analysis of Secondary Efficacy Variables

The secondary efficacy variable partial clearance rate was analyzedusing Cochran-Mantel-Haenszel (CMH) statistics, stratifying by genderand site. The percent change from baseline to EOS in wart count wasanalyzed using analysis of covariance (ANCOVA), controlling for baselinewart count, gender, and analysis site. The proportion of subjects whowere clear prior to or at EOS and remained clear at the end of thefollow-up for recurrence period was summarized by frequency count and95% confidence interval. The time to complete clearance was analyzedusing the log rank test in the context of a Kaplan-Meier survivalanalysis. For analysis of secondary efficacy variables, only the LOCFmethod was used for the ITT population, and observed cases for the PPpopulation. All data from interim visits were analyzed using visitwindows.

The secondary efficacy variables were compared pairwise using Hochberg'smodified Bonferroni procedure.

-   -   If at least one of the active arms was found to be superior to        placebo in the primary efficacy variable of complete clearance        according to Hochberg's modified Bonferroni procedure, the        secondary efficacy variable of partial (>75%) clearance was        compared between each of the active arms and placebo.    -   If the secondary efficacy variable of partial (>75%) clearance        was found to be superior to placebo in either of the active        treatment groups, then the secondary efficacy variable of        percent change from Baseline to EOS in wart count was tested.    -   If the secondary efficacy variable of percent change from        Baseline to EOS in wart count was found to be superior to        placebo in either of the active treatment groups, then the        secondary efficacy variable of complete clearance at EOS and        remained clear at the end of follow-up for recurrence period was        tested.    -   If the secondary efficacy variable of complete clearance at EOS        and remained clear at the end of follow-up for recurrence period        was found to be superior to placebo in either of the active        treatment groups, then the secondary efficacy variable of time        from Baseline to complete clearance was tested.

The percent change from Baseline in EGW count at each post-baselinevisit was summarized by mean, standard deviation, median, and range bytreatment group. The recurrence rate of warts was summarized bytreatment group and study visit using visit windows.

Analysis of Tertiary Efficacy Variables

The tertiary efficacy endpoints, complete clearance rate at EOT andsubject status with respect to at least a 50% reduction in baseline wartcount, were analyzed using Cochran-Mantel-Haenszel (CMH) statistics,stratifying on gender and site.

Visit Windows

For the analysis of wart counts, the data were summarized by analysisvisits. Analysis visits were assigned according to the actual study dayof the evaluation as illustrated in Table 64.

TABLE 64 Visit Windows Evaluation Period Target Analysis Visit Study DayDay Range Baseline 1   Study Day ≤1 Week 2 15  1 < Study Day ≤ 22 Week 429 22 < Study Day ≤ 36 Week 6 43 36 < Study Day ≤ 50 Week 8 57 50 <Study Day ≤ 64 End of Treatment (EOT) —    Study Day ≤64 Week 10 71 64 <Study Day ≤ 78 Week 12 85 78 < Study Day ≤ 92 Week 14 99  92 < Study Day≤ 106 Week 16 113 106 < Study Day ≤ 127 End of Study (EOS) —    StudyDay ≤127 Target Follow-up Period Study Day Analysis Visit Post EOS DayRange Follow-up Week 4 29  1 < Study Day ≤ 43 Follow-up Week 8 57 43 <Study Day ≤ 71 Follow-up Week 12 85 71 < Study Day ≤ 99

All visits (scheduled or unscheduled) were mapped to an analysis visit.If more than 1 evaluation was assigned to an analysis visit, theevaluation with the lowest wart count within the window was used foranalysis. Study day was calculated as the date of evaluation minus thedate of randomization plus one except for the follow up visits. For thefollow up visits, study day was calculated as the date of evaluationminus the date of End of Study (EOS) visit plus one.

Safety Analyses

All safety variables were analyzed using the safety population. Safetyvariables included the following:

-   -   Local skin reactions.    -   Rest periods during the treatment period:        -   The number and percentage by treatment group of subjects who            required a rest period (1 or more).        -   The number of dosing days missed due to rest periods.        -   The number of dosing days prior to the beginning of the            first rest period.    -   Adverse events.    -   Clinical laboratory test results.        Adverse Events

Adverse events were coded using Medical Dictionary for RegulatoryActivities (MedDRA, version 11.0) terminology. A treatment-emergent AEwas defined as an AE that began or worsened in severity after Day 1 andno more than 30 days after the last application of study drug. If an AEhad a completely missing start date, it was considered a “treatmentemergent” event, unless the stop date was prior to the date ofrandomization.

Treatment-emergent AEs and all AEs were summarized for each treatmentgroup by the overall incidence of at least one event, incidence bysystem organ class, and incidence by system organ class and preferredterm. Each subject contributed only once to each of the rates,regardless of the number of occurrences (events) the subjectexperienced.

Treatment-emergent AEs were summarized by severity (mild, moderate, orsevere) and by relationship to study product (related, not related).Events were considered not related to study product if the relationshipwas “not related” or “probably not related”.

Similarly, related events were those that were “probably related” or“related”. An AE was assumed to be related to study drug if therelationship to study drug was unknown. For AEs that occurred more thanonce, the AE that was most related to study drug in that period was usedin the summary of AEs by relationship to study drug categories.Similarly, the AE with the maximum intensity in that period was used inthe summary of AEs by severity. If severity was missing or unknown, itwas assumed to be severe.

The incidence of AEs was summarized for subgroup analysis by gender, byage subgroup, and by number of anatomic locations (i.e., one locationversus multiple). Serious AEs (SAES) and AEs that led to discontinuationfrom the study were listed by subject.

Local Skin Reactions

The LSR intensities were summarized by frequency counts and mean scoreby treatment group and study visit for each LSR type. The LSRs weregraded as follows:

-   -   Erythema (0=None, 1=Faint to mild redness, 2-Moderate redness,        3=Intense redness),    -   Edema (O=None, 1=Mild visible or barely palpable        swelling/induration, 2=Easily palpable swelling/induration        3=Gross swelling/induration),    -   Weeping/Exudate (O=None, 1=Minimal exudate, 2-Moderate exudate,        3=Heavy exudate),    -   Flaking/Scaling/Dryness (O=None, 1=Mild dryness/flaking,        2=Moderate dryness/flaking, 3=Severe dryness/flaking),    -   Scabbing/Crusting (0=None, 1=Crusting, 2=Serous scab, 3-Eschar),    -   Erosion/Ulceration (O=None, 2=Erosion, 3-Ulceration).

Erosion/ulceration intensity was originally collected as 0=None,1=Erosion, and 2=Ulceration. For consistency in the analysis of LSRintensities and sum score, these were recoded as 0=None, 2=Erosion, and3=Ulceration.

The most intense reaction (post-baseline) and incidence of any reaction(post-baseline) for each LSR type were also presented by frequencydistribution and mean score by treatment group. Data were analyzed usingvisit windows.

The LSR sum score (addition of 6 scores) was computed and summarized bytreatment group at each study visit.

Rest Periods

A rest period was a temporary interruption of dosing due to intolerableLSRs or other AEs. Doses missed due to a subject's noncompliance withthe treatment regimen were not considered a rest period. The start of arest period was the first date on which the study medication was notapplied for the reason of “rest period”. The end of the rest period wasthe first date of application following the start of the rest period.The number and percentage of subjects who required a rest period (1 ormore) were analyzed by treatment group using CMH statistics. The numberof dosing days missed due to rest periods and the number of dosing daysprior to the beginning of the first rest period were analyzed using theWilcoxon test. In this analysis, only subjects who experienced a restperiod were included.

Study Patients

Disposition of Subjects

Evaluation Period

Subject disposition for the evaluation period is displayed in Table 65below.

TABLE 65 Subject Disposition - Evaluation Period (ITT Population)Imiquimod Cream Total Subjects, n (%) 3.75% 2.5% Placebo OverallRandomized 204 202 105 511 Completed evaluation^(a) 149 (73.0) 139(68.8) 77 (73.3) 365 (71.4) Not Cleared 89 (43.6) 90 (44.6) 68 (64.8)247 (48.3) Cleared, Ended Study 7 (3.4) 6 (3.0) 2 (1.9) 15 (2.9)Cleared, Entered Follow- 53 (26.0) 43 (21.3) 7 (6.7) 103 (20.2)Discontinued 55 (27.0) 63 (31.2) 28 (26.7) 146 (28.6) evaluation periodReasons for discontinuation during evaluation period, n (%) Safetyreasons (AEs) 3 (1.5) 4 (2.0) 0 7 (1.4) Investigator's request 2 (1.0) 01 (1.0) 3 (0.6) Subject's request (not AE) 11 (5.4) 10 (5.0) 4 (3.8) 25(4.9) Lack of efficacy 0 0 0 0 Noncompliance 2 (1.0) 3 (1.5) 3 (2.9) 8(1.6) Use of concomitant 0 1 (0.5) 0 1 (0.2) Lost to follow-up 35 (17.2)40 (19.8) 19 (18.1) 94 (18.4) Other (not AE)^(b) 2 (1.0) 5 (2.5) 1 (1.0)8 (1.6) AE = adverse event ^(a)Based on investigator assessment (CRFpage 31), includes subjects who (1) cleared prior to or at EOS/Week 16,(2) not cleared at Week 16. One subject in 2.5% treatment group had awart count of zero at EOS but reason for discontinuation was ‘Subject'srequest’ due to concomitant cryotherapy. Another subject in the 2.5%treatment group had a wart count of zero at Week 8 visit but not clearedat EOS. One subject was randomized to the 2.5% treatment group, butincluded in the 3.75% group for safety analysis. One subject in the 2.5%imiquimod group, who discontinue from the study at the subject's requestwas also recorded as discontinued from the study due to an adverseevent.

Of 911 subjects who were screened, 511 (56.1%) were randomized and 400(43.9%) failed screening. The most frequent reason for screen failure(194 subjects [48.5% out of 400 screen failures]) was that the subjectdid not have a clinical diagnosis of external genital/perianal warts anddid not have between 2 and 30 warts located in the inguinal, perinealand perianal areas.

Two hundred and four (204) subjects were randomized into the 3.75%imiquimod treatment group, 202 subjects were randomized into the 2.5%imiquimod treatment group, and 105 subjects were randomized into theplacebo group. Overall, 71.4% of the subjects completed the evaluationstudy, and in the individual treatment groups 73.0%, 68.8%, and 73.3% inthe 3.75% imiquimod, 2.5% imiquimod, and placebo groups, respectively,completed the study. Lost to follow-up, was the most common reason fordiscontinuation from the evaluation period and accounted for withdrawalof at least 17% of the subjects in each treatment group. There was noappreciable difference in the percentages of subjects who were lost tofollow-up or the times at which they became lost to follow-up. Of thesubjects who withdrew from the study, a sizable number of subjectsdiscontinued early, i.e., had no post-Baseline visit: 16 of 55 (29.1%)in the 3.75% imiquimod group, 21 of 63 (33.3%) in the 2.5% imiquimodgroup, and 7 of 28 (25%) in the placebo group. No subjects werediscontinued from the study due to lack of efficacy.

Of the 511 subjects randomized into treatment groups, 222 were male and289 were female. Similar percentages of subjects of males and females ineach treatment group completed the evaluation period. With the exceptionof subjects showing EGW clearance (a higher percentage of femalescompared with males cleared of EGW), disposition characteristics withingenders were similar to those in the overall population.

Follow-Up for Recurrence Period

Subject disposition for the follow-up period is displayed in Table 66below.

TABLE 66 Subject Disposition - Follow-Up Period (ITT Population) TotalImiquimod Cream Subjects, n (%) 3.75% 2.5% Placebo Overall Enteredfollow-up 53 (100) 43 (100) 7 (100) 103 (100) period Completed study, 36(67.9) 30 (69.8) 7 (100) 73 (70.9) no recurrence Subjects with EGW 11(20.8) 8 (18.6) 0 19 (18.4) recurrence Discontinued 6 (11.3) 5 (11.6) 011 (10.7) follow-up period^(a) Reasons for discontinuation duringfollow- up, n (%) Subject's request 1 (1.9) 1 (2.3) 0 2 (1.9) (not AE)Lost to follow-up 5 (9.4) 3 (7.0) 0 8 (7.8) Other (not AE)^(b) 0 1 (2.3)0 1 (1.0) AE - adverse event. ^(a)Excludes subjects discontinued due torecurrence of external genital warts.

Overall, 103 subjects entered the follow-up for recurrence period, 53subjects in the 3.75%® imiquimod treatment group, 43 subjects in the2.5% imiquimod treatment group, and 7 subjects in the placebo group.

Overall, 11 subjects were discontinued from the follow-up period. Of the6 (11.3%) subjects in the 3.75% imiquimod treatment group, 5 (9.4%)subjects were lost to follow-up and 1 (1.9%) was due to the subject'srequest. Five subjects were discontinued from the follow-up period inthe 2.5% imiquimod treatment group, 3 (7.0%) subjects were lost tofollow-up, and 1 (2.3%) each were due to the subject's request or‘other’ (both non-AE). No subjects in the placebo group discontinuedfrom the follow-up period.

Protocol Deviations

Final determination of each subject's status with respect to inclusionin the PP evaluation was made in a joint data review by clinical andstatistical staff prior to unblinding the treatment codes.

A total of 142 subjects had major protocol deviations and were excludedfrom the PP population; 60 in the 3.75% imiquimod treatment group, 58 inthe 2.5% imiquimod treatment group, and 24 in the placebo group). Atotal of 140 subjects were excluded due to lost to follow-up (accountingfor approximately two-thirds of the subjects excluded from the PPpopulation) and treatment noncompliance. Three subjects who werenoncompliant were also excluded from the PP population for additionalreasons: one subject (2.5% imiquimod group) had taken exclusionarymedication, one subject (3.75%) had a wart area <10 mm² and one subject(placebo) had used imiquimod as a prior EGW treatment within theexclusionary period. One subject was excluded from the PP populationbecause the subject received kits from each of the imiquimod treatmentgroups and 1 subject was excluded because they had taken exclusionarymedication.

A total of 4 subjects (all females) received study medication kits fromthe incorrect gender strata. Subject 10-001 received study medicationkit # M5341 (2.5%), Subject 10-009 received study medication kit # M5426(placebo), Subject 10-011 received study medication kit M5427 (3.75%),and Subject 22-013 received study medication kit M5314 (3.75%) insteadof the next available female kit. For all analyses, these 4 subjectswere analyzed according to their actual gender (female).

Efficacy Evaluation

Datasets Analyzed

The number of subjects in each analysis population is presented in Table67 below.

TABLE 67 Number (%) of Subjects in Analysis Populations Imiquimod CreamPopulations 3.75% 2.5% Placebo Overall ITT population 204  202^(a) 105511 PP population 144 144 81 369 Safety population  205^(a)  201^(a) 105511 Follow-up for  51  43 7 103 Recurrence population ^(a)Subject 04/025was originally randomized to the 2.5% imiquimod treatment group;however, at Week 2, the subject incorrectly received a 3.75% imiquimodtreatment group kit assigned to another subject. For the safety analysisthe highest dose received (3.75%) is used and for the efficacy analysis,the original randomized treatment of 2.5% is used.

A total of 511 subjects were included in the ITT and safety population.Of these, 369 subjects were included in the PP population. A total of103 subjects elected to enter the follow-up period and comprised thefollow-up for recurrence population.

Demographic and Other Baseline Characteristics

Prestudy/Baseline Demographics

Demographic and baseline characteristics for the ITT population arepresented in Table 68 below.

TABLE 68 Demographic Summary by Treatment Group—ITT Population ImiquimodCream 3.75% 2.5% Placebo Overall (N = 204) (N = 202) (N = 105) (N = 511)Age in years Mean (SD) 32.8 (11.0) 33,1 (10.1) 33.3 (10.8) 33.1 (10.6)Median 29.5 31.0 30.0 30.0 Minimum, Maximum 15.0, 70.0 18.0, 60.0 19.0,66.0 15.0, 70.0 Sex, n (%) Male 88 (43.1) 85 (42.1) 49 (46.7) 222 (43.4)Female 116 (56.9) 117 (57.9) 56 (53.3) 289 (56.6) Race, n (%) White 141(69.1) 133 (65.8) 76 (72.4) 350 (68.5) Black/African American 55 (27.0)66 (32.7) 27 (25.7) 148 (29.0) Other 8 (4.0%) 3 (1.5%) 2 (2.0%) 13(2.5%) Ethnicity, n (%) Hispanic 12 (5.9) 21 (10.4) 8 (7.6) 41 (8.0)Non-Hispanic 192 (94.1) 181 (89.6) 97 (92.4) 470 (92.0) SD = standarddeviation.

Demographic characteristics were similar among the 3 treatment groups.Slightly more than half of the subjects were female. Overall, 68.5% ofthe subjects were White and more than 89% of the subjects in everytreatment group were non-Hispanic. The mean age ranged from 32.8 yearsin the 3.75% imiquimod treatment group to 33.3 years in the placebogroup. Demographic characteristics in the PP population were similar tothose in the 1 population.

Medical History

The most frequently reported conditions were hypertension (53 subjects),depression (42 subjects), and seasonal allergies (35 subjects).

External Genital Warts Treatment History

Previous EGW treatment was reported by 50.5%, 52.5%, and 47.6% ofsubjects in the 3.75% imiquimod, 2.5% imiquimod, and placebo groups,respectively. Cryotherapy, the most frequently reported treatment, hadbeen performed in 51 (25.0%) subjects in the 3.75% imiquimod treatmentgroup, in 46 (22.8%) of the subjects in the 2.5% treatment group, and in22 (21.0%) of the subjects in the placebo group. Other treatmentsincluded imiquimod (in a total of 45 subjects), acetic acid (in a totalof 33 subjects), laser therapy (in a total of 29 subjects), “other”treatments (in 24 subjects), podophyllin (in 23 subjects),podophyllotoxin (in 21 subjects) and surgical excision (23 subjects),and electrodessication (13 subjects).

Prior and Concomitant Medications

Seventeen subjects (8.3%) in the 3.75% imiquimod treatment group, 20subjects (9.9%©) in the 2.5% treatment group, and 6 subjects (5.7%) inthe placebo group were taking prior medications, i.e., medications thatwere discontinued prior to the date of randomization. The most commonprior medications were antibacterials for systemic use in 2.9% of the3.75% imiquimod treatment group, 2.5% of the 2.5% imiquimod treatmentgroup, and 3.8% of the placebo group.

One hundred thirty-four (65.4%) subjects in the 3.75% imiquimodtreatment group, 121 (60.2%) subjects in the 2.5% imiquimod treatmentgroup, and 63 (60.0%) subjects in the placebo group received one or moreconcomitant medications during this study. The following classes ofconcomitant medication were received by more than 10% of the subjects inone or more of the treatment groups:

-   -   Analgesics, received by 20.5% of the 3.75% imiquimod treatment        group, 20.4% of the 2.5% imiquimod treatment group, and 20.0% of        the placebo group;    -   Antibacterials for systemic use, received by 15.1% of the 3.75%        imiquimod treatment group, 17.4% of the 2.5% imiquimod treatment        group, and 14.3% of the placebo group;    -   Anti-inflammatory and anti-rheumatic products, received by 14.1%        of the 3.75% imiquimod treatment group, 11.9% of the 2.5%        imiquimod treatment group, and 13.3% of the placebo group;    -   Sex hormones and modulators of the genital system, received by        12.7% of the 3.75% imiquimod treatment group, 10.0% of the 2.5%        imiquimod treatment group, and 12.4% of the placebo group;    -   Psychoanaleptics, received by 10.2% of the 3.75% imiquimod        treatment group, 8.0% of the 2.5% imiquimod treatment group, and        8.6% of the placebo group.        Baseline Number of External Genital Warts

A summary of the external genital wart counts at Baseline and otherbaseline data relevant to subjects' EGW are presented in the Table 69for the ITT population.

TABLE 69 Baseline External Genital Warts Data by Treatment Group - ITTPopulation Imiquimod Cream 3.75% 2.5% Placebo Overall (N = 204 (N = 202)(N = 105) (N = 511) Total wart area (mm²) Mean (SD) 150.2 (321.9) 161.1(367.4) 200.7 (374.9) 164.9 (351.4) Median 61 53 61 57 Minimum, Maximum9, 3419 10, 4000 10, 1950 9, 4000 Total wart count Mean (SD) 8.7 (7.5)7.7 (6.3) 7.7 (6.3) 8.1 (6.8) Media 6 5 6 6 Minimum, Maximum 2, 48 2, 302, 29 2, 48 Years Since Diagnosis Mean 4.9 5.8 5.5 5.4 StandardDeviation 7.4 7.6 7.9 7.6 Median 2.0 2.3 2.2 2.2 Minimum, Maximum 0.0,39.4 0.0, 33.4 0.0, 33.4 0.0, 39.4 Anatomic location, 88 85 49 222Males^(a), n Inguinal 24 (27.3) 17 (20.0) 19 (38.8) 60 (27.0) Perineal 6(6.8) 8 (9.4) 3 (6.1) 17 (7.7) Perianal 8 (9.1) 6 (7.1) 5 (10.2) 19(8.6) Glans Penis 9 (10.2) 11 (12.9) 5 (10.2) 25 (11.3) Penis Shaft 71(80.7) 76 (89.4) 39 (79.6) 186 (83.8) Scrotum 19 (21.6) 16 (18.8) 14(28.6) 49 (22.1) Foreskin 0 2 (2.4) 2 (4.1) 4 (1.8) Anatomic location,116 117 56 289 Females^(b), n Inguinal 11 (9.5) 19 (16.2) 4 (7.1) 34(11.8) Perineal 61 (52.6) 53 (45.3) 29 (51.8) 143 (49.5) Perianal 53(45.7) 51 (43.6) 26 (46.4) 130 (45.0) Vulva 86 (74.1) 78 (66.7) 31(55.4) 195 (67.5) Number of treatment anatomic areas, n (%)-Males^(a)Total Males 88 (100) 85 (100) 49 (100) 222 (100) 1 49 (55.7) 48 (56.5)25 (51.0) 122 (55.0) 2 30 (34.1) 25 (29.4) 12 (24.5) 67 (30.2) 3 8 (9.1)10 (11,8) 10 (20.4) 28 (12.6) 4 1 (1.1) 2 (2.4) 2 (4.1) 5 (2.3) Numberof treatment anatomic areas, n (%)-Females^(b) Total Females 116 (100)117 (100) 56 (100) 289 (100) 1 47 (40.5) 53 (45.3) 28 (50.0) 128 (44.3)2 46 (39.7) 48 (41.0) 23 (41.1) 117 (40.5) 3 20 (17.2) 12 (10.3) 4 (7.1)36 (12.5) 4 3 (2.6) 4 (3.4) 1 (1.8) 8 (2.8) SD = standard deviation.^(a)Denominator based on the number of males in treatment group.^(b)Denominator based on the number of females in treatment group.

The mean total wart area was 164.9 mm² overall, and ranged from 150.2mm² in the 3.75% imiquimod treatment group to 200.7 mm² in the placebogroup. The mean total wart count was 8.1 overall, and ranged from 7.7 inthe 2.5% imiquimod treatment group and placebo to 8.7 in the 3.75%imiquimod treatment group.

In males, the most commonly affected areas were the penis shaft (83.8%),the inguinal area (27.0%), and the scrotum (22.1%). In females, the mostcommonly-affected areas were the vulva (67.5%), the perineal area(49.5%), and the perianal area (45.0%). More than 50% of subjects in thefemale subgroup and more than 40% of subjects in the male subgroup hadtwo or more anatomic locations affected with warts at Baseline.

Measurements of Treatment Compliance

Compliance was based on the number of applications received (where arest period day was counted as an application) divided by the number ofintended applications, or by the number of packets used (where a restperiod day was counted as a packet used) divided by the number ofpackets intended to be used per the protocol-defined treatment regimen,whichever was greater. Noncompliance with the treatment regimen wasdefined as compliance less than 75% or greater than 125%.

The overall mean treatment compliance was 83.2% in the 3.75% imiquimodtreatment group, 86.5% in the 2.5% imiquimod treatment group, and 91.1%in the placebo group). Of the 142 subjects excluded from the PPpopulation, 140 were the result of noncompliance with the treatmentregimen, including many subjects who were lost to follow-up. Compliancerates were slightly higher in subjects who cleared their EGW during thestudy (87.7%, 91.8%, and 97.8% in the 3.75% imiquimod, 2.5% imiquimod,and placebo group, respectively) compared with subjects who did notclear (81.1%, 84.5%, and 90.4% in the 3.75% imiquimod, 2.5% imiquimod,and placebo group, respectively).

Analysis of Efficacy

Complete Clearance Rate of all Warts

Complete Clearance Rates at End of Study

The primary efficacy variable in this study was the proportion ofsubjects with complete clearance of all warts (those present at Baselineand new warts) at EOS (ie, 8 weeks after EOT). The primary analysis wasperformed on the ITT population with imputation (LOCF) for missing datapoints. The PP population analysis used observed cases only. The resultsof these analyses for the ITT population are shown in Table 70. Resultsare presented graphically for the ITT population in FIG. 15.

TABLE 70 Proportion of Subjects with Complete Clearance of Warts at theWeek 16/End of Study Visit Imiquimod Cream 3.75% 25% Placebo ITTPopulation (LOCF) n/N^(a) (%) 60/204 (29.4) 50/202 (24.8) 9/105 (8.6)95% CI 23.3, 36.2 19.0, 31.3 4.0, 15.6 P value vs placebo <0.001**<0.001** — P value vs 2.5%   0.187  imiquimod cream Males n/N^(a) (%)15/88 (17.0) 13/85 (15.3) 2/49 (4.1) 95% CI 9.9, 26.6 8.4, 24.7 0.5,14.0 P value vs placebo   0.019**   0.034** P value vs 2.5%   0.639 imiquimod cream Females n/N^(a) (%) 45/116 (38.8) 37/117 (31.6) 7/56(12.5) 95% CI 29.9, 48.3 23.3, 40.9 5.2, 24.1 P value vs placebo<0.001**   0.012** P value vs 2.5%   0.204  imiquimod cream LOCF = lastobservation carried forward, 95% CI = 95% confidence interval ^(a)n/N =number of subjects with complete clearance at end of study divided bythe number of subjects analyzed. P values are fromCochran-Mantel-Haenszel test, stratified by gender and analysis site(overall population) or stratified by analysis site (gender subgroups,taking 2 treatment groups at a time. P values marked with **arestatistically significant using Hochberg's modified Bonferroniprocedure. Confidence intervals were calculated using the exact binomialstatistics. Breslow-Day P values for ITT Population (LOCF,) males, are3.75% Imiquimod Cream vs Placebo = 0.933, 2.5% Imiquimod Cream vsPlacebo = 0.691, and 3.75% Imiquimod Cream vs 2.5% Imiquimod Cream =0.773. Breslow-Day P values for ITT Population (LOCF), females, are3.75% Imiquimod Cream vs Placebo = 0.731, 2.5% Imiquimod Cream vsPlacebo = 0.757, and 3.75% Imiquimod Cream vs 2.5% Imiquimod Cream =0.942.

In the ITT population, the rate of complete clearance of EGW at EOS wassignificantly higher (P<0.001) in the active treatment groups; 29.4% inthe 3.75% imiquimod group and 24.8% in the 2.5% imiquimod group,compared with placebo (8.6%). As shown in the Table above, subjects inthe 335% imiquimod group had a higher rate of complete clearance thansubjects in the 2.5% imiquimod group. However, the difference betweenthe 2 active treatment groups was not statistically significant(P=0.187).

Results were similar in the by-gender analyses. The complete clearancerates at EOS were statistically significantly higher in the 2 activetreatment groups compared with placebo for both genders. In alltreatment groups, the complete clearance rates were consistently higherin females than in males.

Due to deviations from GCP, an additional analysis was run in which 2study sites (Sites 13 and 18) were excluded from the primary analysis.Removal of the efficacy data from these 2 sites does not materiallyimpact the results: the primary analyses, complete clearance rates ofactives compared to placebo are numerically increased.

Rates of complete clearance at EOS in the ITT population are illustratedin FIG. 15.

The primary efficacy variable was analyzed for the PP population,overall and by gender, using observed cases (OC). Results for the PPpopulation are shown in Table 71.

TABLE 71 Proportion of Subjects with Complete Clearance of Warts at theWeek 16/End of Study Visit - PP Population (Observed Cases) ImquimodCream 3.75% 2.5% Placebo PP population (OC), at EOS n/N^(a) (%) 49/144(34.0) 43/144 (29.9) 9/81 (11.1) 95% confidence interval 26.3, 42.422.5, 38.0 5.2, 20.0 P value vs placebo <0.001** <0.001** — P value vs2.5%   0.243  — imiquimod cream Males n/N^(a) (%) 12/59 (20.3) 12/64(18.8) 2/36 (5.6) 95% confidence interval 11.0, 32.8 10.13, 30.5 0.7,18.7 P value vs placebo 0.026**   0.011** P value vs 2.5%   0.568 imiquimod cream Females n/N^(a) (%) 37/85 (43.5) 31/80 (38.8) 7/45(15.6) 95% confidence interval 32.8, 54.7 28.1, 50.3 6.5, 29.5 P valuevs placebo   0.002**   0.009** P value vs 2.5%   0.424  imiquimod cream95% CI 95% confidence interval, OC = observed cases. ^(a)n/N = number ofsubjects with complete clearance at end of study divided by the numberof subjects analyzed. P values are from Cochran-Mantel-Haenszel test,stratified by gender and analysis site (overall population) orstratified by analysis site (gender subgroups, taking 2 treatment groupsat a time. P values marked with **are statistically significant usingHochberg's modified Bonferroni procedure. Confidence intervals werecalculated using the exact binomial distribution. Complete clearance wascarried forward once achieved.

In the PP population, overall, the complete clearance rates at EOS werehigher than those in the ITT population for all treatment groups: 34.0%in the 3.75% imiquimod group, 29.9% in the 2.5% imiquimod group, and11.1% in the placebo group. The larger responses in the active treatmentgroups were statistically significant compared with placebo (P<0.001 forthe active treatment groups). As was the case in the ITT population, therate of complete clearance was larger in the 3.75% imiquimod group thanin the 2.5% imiquimod group, but the difference between the 2 activetreatment groups was not statistically significant.

Results were similar in the by-gender analyses. In all treatment groupsin the PP population, the complete clearance rates at EOS wereconsistently higher in females than in males. Complete clearance rateswere statistically significantly higher in the 2 active treatment groupscompared with placebo for both genders.

Rates of complete clearance at EOS in the PP population are illustratedin FIG. 16.

Complete Clearance Rates at End of Treatment

A summary of the complete clearance rate at EOT for the ITT population,overall and by gender, is provided in Table 72.

TABLE 72 Proportion of Subjects with Complete Clearance of Warts at Endof Treatment - ITT Population (LOCF) Imiquimod Cream 3.75% 2.5% PlaceboITT Population (LOCF) n/N^(a) (%) 32/204 (15.7) 28/202 (13.9) 4/10 5(3.8) 95% CI 11.0, 21.4 9.4, 19.4 1.0, 9.5 P value vs placebo 0.002**0.012** — P value vs 2.5% 0.460  — — imiquimod cream Males n/N^(a) (%)8/88 (9.1) 6/85 (7.1) 1/49 (2.0) 95% CI 4.0, 17.1 2.6, 14.7 0.1, 10.9 Pvalue vs placebo 0.092  0.222  — P value vs 2.5% 0.547  — — imiquimodcream Females n/N^(a) (%) 24/116 (20.7) 22/117 (18.8) 3/56 (5,4) 95% CI137, 29.2 12.2, 27.1 1.1, 14.9 P value vs placebo 0.009** 0.028** — Pvalue vs 2.5% 0.616  — — imiquimod cream LOCF = last observation carriedforward, 95% CI = 95% confidence interval. ^(a)n/N = number of subjectswith complete clearance at end of treatment divided by the number ofsubjects analyzed. P values are from Cochran-Mantel-Haenszel test,stratified by gender and analysis site (overall population) orstratified by analysis site (gender subgroups), taking 2 treatmentgroups at a time. P values marked with **are statistically significantusing Hochberg's modified Bonferroni procedure. Confidence intervalswere calculated using the exact binomial distribution.

At Week 8/EOT, 15.7% of subjects in the 3.75% imiquimod group, 13.9% ofsubjects in the 2.5% imiquimod group, and 3.8% of subjects in theplacebo group had attained complete clearance. The overall completeclearance rate at EOT was significantly higher in the 3.75% imiquimodgroup (P=0.002) and in the 2.5% imiquimod group (P 0.012) compared withthe placebo group. The clearance rate in the 3.75% imiquimod group wasslightly higher than in the 2.5% imiquimod group; however, thedifference was not statistically significant.

The complete clearance rate at EOT was significantly higher in theactive treatment groups compared with placebo only in the femalesubgroup. In all treatment groups, the complete clearance rates wereconsistently higher in females than in males. Slightly higherpercentages of males in the 3.75% imiquimod group achieved completeclearance than those in the 2.5% imiquimod group.

A summary of the complete clearance at EOT for the PP population isprovided in Table 73.

TABLE 73 Proportion of Subjects with Complete Clearance of Warts at Endof Treatment - PP Population (Observed Cases) Imiquimod Cream 3.75% 2.5%Placebo PP Population (QC), at EOT nfli^(a) (%) 26/144 (18.1) 24/144(16.7) 4/81 (4.9) 95% CI 12.1, 25.3 11.0, 23.8 1.4, 12.2 P value vsplacebo 0.010** 0.019** — P value vs 2.5% 0.602  — — imiquimod creamMales n/N^(a) (%) 7/59 (11.9) 6/64 (9,4) 1/36 (2.8) 95% CI 4.9, 22.93.5, 19.3 0.1, 14.5 P value vs placebo 0.206  0.250  — P value vs 2.5%0.400  — — imiquimod cream Females n/N^(a) (%) 19/85 (22.4) 18/80 (22.5)3/45 (6.7) 95% CI 14.0, 32.7 13.9, 33.2 1.4, 18.3 P value vs placebo0.024** 0.041** — P value vs 2.5% 0.934  — — imiquimod cream 95% CI =95% confidence interval, OC = observed cases ^(a)n/N = number ofsubjects with complete clearance at end of treatment divided by thenumber of subjects analyzed. P values are from Cochran-Mantel-Haenszeltest, stratified by gender and analysis site (overall population) orstratified by analysis site (gender subgroups), taking 2 treatmentgroups at a time. P values marked with **are statistically significantusing Hochberg's modified Bonferroni procedure. Confidence intervalswere calculated using the exact binomial distribution. Completeclearance was carried forward once achieved.

In the PP population, the EOT complete clearance rate was significantlyhigher in both active treatment groups compared with placebo (P=0.010for 3.75% imiquimod vs placebo; and P=0.019 for 2.5% imiquimod vsplacebo). The difference between the active treatment groups was notstatistically significant.

In the PP population, complete clearance rates for males and femaleswere higher than those in the population. Complete clearance rates inthe female subgroup in both active treatment groups were essentially thesame and were significantly higher compared with those in the placebogroup. A slightly higher percentage of males in the 3.75% imiquimodgroup achieved complete clearance than those in the 2.5% imiquimodgroup. In both treatment groups in males, the difference in clearancerate was not statistically significant when compared to placebo. In alltreatment groups, the complete clearance rates were consistently higherin females than in males.

Complete Clearance Rates by Visit Week

A by-visit summary of complete clearance rates in the ITT populationduring the evaluation period is shown graphically in FIG. 17.

As shown in FIG. 17, the complete clearance rate was higher in theimiquimod treatment groups compared with placebo at all assessment timepoints after Week 4, and the differences were statistically significantat Week 8 (EOT) and thereafter. This includes the Week 8/end oftreatment assessment and the Week 16/end of study assessment.

In female subjects, the complete clearance rate was significantly higherin the 3.75% imiquimod group compared with placebo at all assessmenttime points after Week 6. The complete clearance rate was significantlyhigher in the 2.5% imiquimod group compared with placebo at Weeks 8, 10and 16. The difference between the active treatment groups was notstatistically significant at any time point during the evaluationperiod. In male subjects, the complete clearance rate was significantlyhigher in the 3.75% group compared with placebo at all assessment timepoint from Week 10 to Week 16. The complete clearance rate wassignificantly higher in the 2.5% imiquimod group compared with placeboat Weeks 14 and 16. The difference between the active treatment groupswas not statistically significant at any time point during theevaluation period.

A by-visit summary of complete clearance rates in the PP populationduring the evaluation period is shown in FIG. 18.

Results in the PP population were similar to those in the ITTpopulation. The complete clearance rate was significantly higher in theactive treatment groups compared with placebo at all assessment timepoints after Week 6. The difference in clearance rate between the 2active treatments was not statistically significant.

In female subjects, the complete clearance rate was significantly higherin the 3.75% and 2.5% imiquimod groups compared with placebo at Week 8and Week 16. The difference between the active treatment groups was notstatistically significant at any time point during the evaluationperiod. In male subjects, the complete clearance rate was significantlyhigher in the 3.75% group compared with placebo at Week 10, Week 14 andWeek 16. The complete clearance rate was significantly higher in the2.5% imiquimod group compared with placebo at Week 16. The differencebetween the active treatment groups was not statistically significant atany time point during the evaluation period.

Partial Clearance Rates

Partial (≥75%) Clearance Rates at End of Study

The proportion of subjects, overall and by gender, who had a partialclearance (≥75% reduction from Baseline in wart count) during the studyis summarized in Table 74 for the ITT population. Partial clearance wasdefined as at least a 75% reduction in the number of warts in thetreatment area compared with Baseline.

TABLE 74 Proportion of Subjects with Partial (≥75%) Clearance at End ofStudy, ITT Population Imiquimod Cream 3.75% 2.5% Placebo ITT Population(LOCF) at EOS n/N^(a) (%) 79/204 (38.7) 63/202 (31.2) 11/105 (10.5) 95%CI 32.0, 45.8 24.9, 38.1 5.3, 18.0 P value vs Placebo <0.001**<0.001**   — P value vs 2.5% Imiquimod   0.078  — — Cream Males n/N^(a)(%)  21/88 (23.9) I9/85 (22.4)  3/49 (6.1) 95% CI 15.4, 34.1 14.0, 32.71.3, 16.9 P value vs Placebo   0.008** 0.013** P value vs 2.5% Imiquimod  0.776  Cream Females n/N^(a) (%) 58/116 (50.0) 44/117 (37.6)  8/56(14.3) 95% CI 40.6, 59.4 28.8, 47.0 6.4, 26.2 P value vs Placebo<0.001** 0.002** P value vs 2.5% Imiquimod   0.050** Cream 95% CI = 95%confidence interval ^(a)n/N = number of subjects with complete clearanceat end of study divided by the number of subjects analyzed. Partialclearance was defined as at least a 75% reduction in the number of wartsin the treatment area compared with Baseline. P values are fromCochran-Mantel-Haenszel test, stratified by gender and analysis site(gender subgroups), or stratified by analysis site (gender subgroups)taking 2 treatment groups at a time. The P values marked with ** arestatistically significant using Hochberg's modified Bonferroniprocedure. Confidence intervals were calculated using the exact binomialdistribution.

In the ITT population, the difference in the partial (≥75%) clearancerate at EOS between each of the imiquimod treatment groups and placebowas statistically significant (P≤0.001). The partial (≥75%) clearancerate was higher in the 3.75% imiquimod group than in the 2.5% imiquimodgroup, but the difference between the 2 active treatment groups was notstatistically significant.

In the by-gender analyses, the ≥75% clearance rate at EOS wassignificantly higher in both of the active treatment groups comparedwith placebo for both males and females. The ≥75% clearance rate in thefemale subgroup was significantly higher in the 3.75% imiquimod groupthan in the 2.5% imiquimod group. In all treatment groups, the ≥75%clearance rates were consistently higher in females than in males.

Rates of partial (≥75%) clearance at EOS in the ITT population areillustrated in FIG. 19.

A summary of the partial (≥75%) clearance rate at EOS for the PPpopulation, overall and by gender, is presented in Table 75. The ≥75%clearance rates at EOS are presented graphically in FIG. 20 for the PPpopulation.

TABLE 75 Proportion of Subjects with Partial (>75%) Clearance at End ofStudy-PP Population (Observed Cases) Imiquimod Cream 3.75% 2.5% PlaceboPP Population (OC), at EOS n/N^(a) (%) 65/144 (45.1) 55/144 (38.2) 11/81(13.6) 95% CI 36.8, 53.6 30.2, 46.7 7.0, 23.0 P value vs placebo <0.001.** <0.001**   — P value vs 2.5%   0.128  — — imiquimod creamMales n/N^(a) (%)  16/59 (27.1)  18/64 (28.1) 3/36 (8.3) 95% CI 16.4,40.3 17.6, 40.8 1.8, 22.5 P value vs placebo   0.011** 0.014** — P valuevs 2.5%   0.696  — — imiquimod cream Females n/N^(a) (%)  49/85 (57.6) 37/80 (46.3)  8/45 (17.8) 95% CI 46.4, 68.3 35.0, 57.8 8.0, 32.1 Pvalue vs placebo <0.001** 0.001** — P value vs 2.5%   0.112  — —imiquimod cream 95% CI = 95% confidence interval, OC = observed cases^(a)n/N = number of subjects with complete clearance at end of studydivided by the number of subjects analyzed. Partial clearance wasdefined as at least a 75% reduction in the number of warts in thetreatment area compared with Baseline. P values are fromCochran-Mantel-Haenszel test, stratified by gender and analysis site(overall population) or stratified by analysis site (gender subgroups),taking 2 treatment groups at a time. P values marked with ** arestatistically significant using Hochberg's modified Bonferroniprocedure. Confidence intervals were calculated using the exact binomialdistribution statistics.

In the PP population, the partial (≥75%) clearance rate at EOS washigher in the active treatment groups than in the placebo group. Thedifference between each of the imiquimod treatment groups and placebowas statistically significant (P<0.001). There was no statisticallysignificant difference in partial (≥75%) clearance rate between theactive treatment groups. The partial (≥75%) clearance rates werestatistically significantly higher in the 3.75% imiquimod group comparedwith placebo at all analysis time points after Week 4; results of theanalysis over time are presented below.

As in the overall PP population, the ≥75% clearance rate wassignificantly higher with 3.75% imiquimod and with 2.5% imiquimod versusplacebo in either gender. There was no statistically significantdifference between the active treatment groups in either gender.

Rates of partial (≥75%) clearance at EOS in the PP population areillustrated in FIG. 20.

Partial (≥75%) Clearance Rates at End of Treatment

The proportion of subjects who had a 75% or greater reduction fromBaseline in wart count at EOT is summarized in Table 76 for the ITTpopulation.

TABLE 76 Proportion of Subjects with Partial (≥75%) Clearance at End ofTreatment-ITT Population (LOCF) Imiquimod Cream 3.75% 2.5% Placebo ITTPopulation (LOCF) at EOT n/N^(a) (%) 60/204 (29.4) 44/202 (21.8) 8/105(7.6) 95% CI 23.3, 36.2 16.3, 28.1 3.3, 14.5 P value vs placebo <0.001**0.003** — P value vs 2.5% imiquimod 0.054 — — cream Males n/N^(a) (%) 19/88 (21.6)  11/85 (12.9)  1/49 (2.0) 95% CI 13.5, 31.6  6.6, 22.00.1, 10.9 P value vs placebo 0.002** 0.029** P value vs 2.5% imiquimod0.134 cream Females n/N^(a) (%) 41/116 (35.3) 33/117 (28.2)  7/56 (12.5)95% CI 26.7, 44.8 20.3, 37.3 5.2, 24.1 P value vs placebo 0.001**0.027** P value vs 2.5% imiquimod 0.193 cream LOCF = last observationcarried forward, 95% CI = 95% confidence interval. ^(a)n/N—number ofsubjects with complete clearance at end of treatment divided by thenumber of subjects analyzed. Partial clearance was defined as at least a75% reduction in the number of warts in the treatment area compared withBaseline. P values are from Cochran-Mantel-Haenszel test, stratified bygender and analysis. site (overall population) or stratified by analysissite (gender subgroups), taking 2 treatment groups at a time. P valuesmarked with ** are statistically significant using Hochberg's modifiedBonferroni procedure. Confidence intervals were calculated using theexact binomial statistics.

In the overall ITT population, the ≥75% clearance rate at EOT wassignificantly higher in the active treatment groups than in the placebogroup. The difference between the active treatment groups was notstatistically significant.

The ≥75% clearance rate at EOT was significantly higher with both activetreatment groups compared with placebo in either gender. There was nosignificant difference between 3.75% and 2.5% imiquimod in either gendersubgroup.

The partial (≥75%) clearance rate at EOT for the PP population isprovided in Table 77.

TABLE 77 Proportion of Subjects with Partial (≥75%) Clearance at End ofTreatment-PP Population (Observed Cases) Imiquimod Cream 3.75% 2.5%Placebo PP Population (OC), EOT n/N^(a) (%) 51/144 (35.4)  39/144 (27.1)8/81 (9.9)  95% CI 27.6, 43.8 20.0, 35.1 4.4, 18.5 P value vs placebo<0.001** 0.003** — P value vs 2.5% 0.047** — — imiquimod cream Malesn/N^(a) (%) 16/59 (27.1)  11/64 (17.2) 1/36 (2.8)  95% CI 16.4, 40.3 8.9, 28.7 0.1, 14.5 P value vs placebo 0.007** 0.031** — P value vs2.5% 0.090 — — imiquimod cream Females n/N^(a) (%) 35/85 (41.2)  28/80(35.0) 7/45 (15.6) 95% CI 30.6, 52.4 24.7, 46.5 6.5, 29.5 P value vsplacebo 0.003** 0.036** — P value vs 2.5% 0.220 — — imiquimod cream 95%CI = 95% confidence interval, OC = observed cases, EOT = end oftreatment ^(a)n/N = number of subjects with complete clearance at end oftreatment divided by the number of subjects analyzed. Partial clearancewas defined as at least a 75% reduction in the number of warts in thetreatment area compared with Baseline. P values are fromCochran-Mantel-Haenszel test, stratified by gender and analysis site(overall population) or stratified by analysis site (gender subgroups),taking 2 treatment groups at a time. The P values marked with ** arestatistically significant using Hochberg's modified Bonferroniprocedure. Confidence intervals were calculated using the exact binomialdistribution statistics.

In the overall PP population, the ≥75% clearance rate at EOT wassignificantly higher in the active treatment groups than in the placebogroup. The partial (≥75%) clearance rate in the 3.75% imiquimod groupwas significantly higher (P=0.047) than that in the 2.5% imiquimodtreatment group.

The ≥75% clearance rate at EOT was significantly higher with both activetreatment groups compared with placebo for both genders. There was nosignificant difference between 3.75% and 2.5% imiquimod groups in eithergender.

Partial (≥75%) Clearance Rates by Analysis Visit

Over the course of the study, the partial (≥75%) clearance rates werestatistically significantly higher in the 3.75% and 2.75% imiquimodgroup compared with placebo at all analysis time points after Week 6,and were significantly higher for 3.75% compared with 2.5% imiquimod atWeeks 6, 12, and 14.

In both genders, the difference between each of the imiquimod treatmentgroups and placebo was statistically significant at Week 16. In thefemale subgroup, the difference between the active treatment groups wasstatistically significant (P=0.050).

The partial (≥75%) clearance rates were statistically significantlyhigher in the 3.75% and 2.75% imiquimod groups compared with placebo atall analysis time points after Week 8, and were significantly higher for3.75% imiquimod group compared with 2.5% imiquimod at Weeks 6 and 10.

Subjects with at Least a 50% Reduction in Wart Count at End of Study

Table 78 provides a summary of the ≥50% clearance rate at EOS for theITT population (overall and by gender). The results are presentedgraphically in FIG. 21.

TABLE 78 Proportion of Subjects with ≥50% Clearance at End of Study-ITTPopulation (LOCF) Imiquimod Cream 3.75% 2.5% Placebo ITT Population(LOCF) at EOS n/N^(a) (%) 101/204 (49.5) 87/202 (43.1) 21/105 (20.0) 95%CI 42.5, 56.6 36.1, 50.2 12.8, 28.9 P value vs placebo <0.001** <0.001**— P value vs 2.5% 0.154 — — imiquimod cream Males n/N^(a) (%)  27/88(30.7)  29/85 (34.1)  5/49 (10.2) 95% CI 21.3, 41.4 24.2, 45.2  3.4,22.2 P value vs placebo 0.007** 0.002** P value vs 2.5% 0.617 imiquimodcream Females n/N^(a) (%)  74/116 (63.8) 58/117 (49.6)  16/56 (28.6) 95%CI 54.4, 72.5 40.2, 59.0 17.3, 42.2 P value vs placebo <0.001** 0.009**P value vs 2.5% 0.027** imiquimod cream LOCF—last observation carriedforward, 95% CI = 95% confidence interval. ^(a)n/N—number of subjectswith complete clearance at end of study divided by the number ofsubjects analyzed. 50% clearance is defined as at least a 50% reductionin the number of warts in the treatment area compared with Baseline. Pvalues are from Cochran-Mantel-Haenszel test, stratified by gender andanalysis site (overall population) or stratified by analysis site(gender subgroups), taking 2 treatment groups at a time. P values markedwith ** are statistically significant using Hochberg's modifiedBonferroni procedure. Confidence intervals were calculated using theexact binomial distribution statistics.

In the overall ITT population, the rate of ≥50% clearance of EGW at EOSwas significantly higher in each of the imiquimod treatment groupscompared with placebo. The ≥50% clearance rate was higher in the 3.75%imiquimod group than in the 2.5% imiquimod group, but the differencebetween the 2 active treatment groups was not statistically significant.

The ≥50% clearance rate at EOS was significantly higher with both activetreatment groups compared with placebo for both genders. The ≥50%clearance rate at EOS was significantly higher in the 3.75% imiquimodgroup compared with the 2.5% imiquimod group for females only. In males,the ≥50% clearance rate was higher in the 2.5% imiquimod group than inthe 3.75% imiquimod group. However, the difference was not statisticallysignificant.

Results in the PP population (overall and by gender) were similar toresults in the ITT population.

Subjects with ≥50% Reduction in Wart Count at End of Treatment

Table 79 provides a summary of the ≥50% clearance rate at EOT for theITT population (overall and by gender).

TABLE 79 Proportion of Subjects with ≥50% Clearance at End of Treatment-ITT Population (LOCF) Imiquimod Cream 3.75% 2.5% Placebo ITT Population(LOCF) at EOT n/N^(a) (%) 89/204 (43.6) 74/202 (36.6) 18/105 (17.1) 95%CI 36.7, 50.7 30.0, 43.7 10.5, 25.7 P value vs placebo <0.001** <0.001**P value vs 2.5% 0.103 imiquimod cream Males n/N^(a) (%)  31/88 (35.2) 25/85 (29.4)  5/49 (10.2) 95% CI 25.3, 46.1 20.0, 40.3  3.4, 22.2 Pvalue vs placebo <0.001** 0.012** P value vs 2.5% 0.412 imiquimod creamFemales n/N^(a) (%) 58/116 (50.0) 49/117 (41.9)  13/56 (23.2) 95% CI40.6, 59.4 32.8, 51.4 13.0, 36.4 P value vs placebo <0.001** 0.016** Pvalue vs 2.5% 0.152 imiquimod cream LOCF = last observation carriedforward, 95% CI = 95% confidence interval. ^(a)n/N of subjects withcomplete clearance at end of treatment divided by the number of subjectsanalyzed. 50% clearance was defined as at least a 50% reduction in thenumber of warts in the treatment area compared with Baseline. P valuesare from Cochran-Mantel-Haenszel test, stratified by gender and analysissite (overall population) or stratified by analysis site (gendersubgroups), taking 2 treatment groups at a time. The P values markedwith ** are statistically significant using Hochberg's modifiedBonferroni procedure. Confidence intervals were calculated using theexact binomial distribution statistics.

In the overall ITT population, the ≥50% clearance rate at EOT wassignificantly higher in the active treatment groups than in the placebogroup. The difference between the active treatment groups was notstatistically significant. The ≥50% clearance rate at EOT wassignificantly higher with both active treatment groups compared withplacebo for both gender subgroups. There was no significant differencebetween 3.75% and 2.5% imiquimod in either gender. In all treatmentgroups, the ≥50% clearance rates at EOT were higher in females than inmales.

Results were similar in the PP population. In the overall PP population,the rate of ≥50% clearance of EGW at EOT was significantly higher in theactive treatment groups compared to placebo. In both the male and femalesubgroups, the ≥50% clearance rate was significantly higher in both ofthe active treatment groups compared with placebo.

Subjects with ≥50% Reduction in Wart Count by Analysis Week

As shown in FIG. 22 for the overall ITT population, the differencebetween each of the imiquimod treatment groups and placebo wasstatistically significant at Week 16 (P<0.001 for 3.75% imiquimod and2.5% imiquimod vs placebo), and at all post-Baseline assessment timepoints after Week 4. The ≥50% clearance rate in the 3.75% imiquimodgroup was higher than that in the 2.5% imiquimod treatment group at Endof Study however the difference was not statistically significant.

In both genders, the difference between each of the imiquimod treatmentgroups and placebo was statistically significant at Week 16. In thefemale subgroup, the difference between the active treatment groups wasstatistically significant (P=0.027).

Results in the PP population were similar to those in the ITTpopulation. Compared with placebo, the ≥50% clearance rate wassignificantly higher in both active treatment groups at all analysistime points after Week 4. The ≥50% clearance rate in the 3.75% imiquimodgroup was higher than that in the 2.5% imiquimod treatment group at Endof Study however the difference was not statistically significant.

Wart Counts and Change and Percent Change from Baseline in Wart Counts

Summaries of the EGW counts, change from Baseline in EGW counts, andpercent change from Baseline in EGW counts over the course of the studyare presented in Table 80 below. The mean percent changes in EGW countsover time are presented graphically in FIG. 23.

TABLE 80 Summary of External Genital Wart Count from Baseline to End ofTreatment/End of Study-ITT Population (LOCF) Imiquimod Cream 3.75% 2.5%Placebo (N = 204) (N = 202) (N = 105) Baseline Mean   8.7 (7.5)   7.7(6.3)   7.7 (6.3) Median 6 5 6 Min, Max  2, 48  2, 30    2, 29 P valuevs Placebo 0.180 0.727 P value vs 2.5% Imiquimod 0.158 Week 8/EOT Mean  5.5 (7.2)   5.3 (5.6)   7.2 (6.6) Median 3 3 5 Min, Max  0, 51  0, 25   0, 30 Week 16/EOS Mean   5.0 (7.3)   4.7 (5.7)   7.1 (6.8) Median 3 34 Min, Max  0, 65  0, 29    0, 31 Change from Baseline to EOS Mean −3.7(7.1) −3.0 (4.9) −0.6 (3.7) Median −2 −1 0 Min, Max −43, 40   −30, 7   −15, 11 P value vs Placebo <0.001** <0.001** P value vs 2.5% Imiquimod0.643 Percent Change from Baseline to EOS Mean −40.9 (56.9) −37.7 (46.2) −7.8 (46.8) Median −46.8 −19.1 0.0 Min, Max −100, 160   −100, 67   −100, 183 P value vs Placebo <0.001** <0.001** P value vs 2.5% Imiquimod0.641 P values are from Cochran-Mantel-Haenszel test, stratified bygender and analysis site, taking 2 treatment groups at a time. Changefrom Baseline is calculated as the post-Baseline value minus theBaseline value. Change from Baseline P values are from analysis ofcovariance (ANCOVA), controlling for Baseline wart count, gender, andanalysis site. The P values marked with ** are statistically significantusing Hochberg's modified Bonferroni procedure.

The mean EGW count at Baseline was similar between all the treatmentgroups for the ITT population. At EOT the EGW counts were lowest in the3.75% imiquimod group and highest in the placebo group. At EOS the EGWcounts were lowest in the 2.5% imiquimod group and highest in theplacebo group. At EOS, the mean change from Baseline was significantlygreater in the active treatment groups compared with placebo. Thedifference in mean change between the active treatment groups was notstatistically significant.

In the gender subgroups, the Baseline EGW counts were higher in the3.75% imiquimod group and 2.75% imiquimod group in both genders comparedwith placebo however the difference was not statistically significant.The mean change and mean percent change from Baseline in EGW count wassignificantly larger for both active treatment groups versus placebo inmales and in females.

As shown in FIG. 23 for the ITT population, the mean percent decreasefrom Baseline in wart count in the 2 active treatment groups wasconsistently larger than placebo, and the differences between the 2active treatment groups compared with placebo were statisticallysignificant at all post-Baseline analysis time points after Week 4. Thedifferences between the 3.75% imiquimod and 2.5% imiquimod groups werenot statistically significant at any time during the study.

For the PP population, summaries of the EGW counts, change from Baselinein EGW counts, and percent change from Baseline in EGW counts over thecourse of the study are presented in Table 81.

TABLE 81 Summary of External Genital Wart Count from Baseline to End ofTreatment and End of Study-PP Population (Observed Cases) ImiquimodCream 3.75% 2.5% Placebo Baseline N 144 144 81 Mean   8.4 (7.2) 7.6(6.4) 7.8 (6.3) Median 6 5 6 MM, Max    2, 32  2, 30  2, 29 P value vsPlacebo 0.174 0.726 P value vs 2.5% Imiquimod 0.340 End of Treatment(EOT) N 119 125 72 Mean   5.3 (7.7) 4.7 (5.2) 7.3 (6.3) Median 3 3 5Min, Max    0, 51  0, 25  0, 23 End of Study (EOS) N 87 93 65 Mean   6.4(9.0) 5.2 (5.8) 7.8 (7.0) Median 4 3 6 Min, Max    0, 65  0, 29  0, 31Change from Baseline at EOS N 87 93 65 Mean −3.1 (7.3) −3.0 (5.5)   0.2(3.7) Median −2 −1 0 Min, Max −25, 40 −30, 5   −15, 11 P value vsPlacebo 0.024** <0.001** P value vs 2.5% Imiquimod 0.208 Percent Changefrom Baseline at EOS N 87 93 65 Mean −30.6 (56.2) −28.9 (40.8)    2.9(45.9) Median −33.3 −20.8 0.0 Min, Max −100, 160 −100, 67   −100, 183 Pvalue vs Placebo <0.001** <0.001** P value vs 2.5% Imiquimod 0.346 Pvalues are from Cochran-Mantel-Haenszel test, stratified by gender andanalysis site, taking 2 treatment groups at a time. Change from Baselineis calculated as the post-Baseline value minus the Baseline value.Change from Baseline P values are from analysis of covariance (ANCOVA),controlling for Baseline wart count, gender, and analysis site. The Pvalues marked with ** are statistically significant using Hochberg'smodified Bonferroni procedure.

The mean EGW count at Baseline was similar across the treatment groupsfor the PP population. At both EOT and EOS, the EGW counts were lowestin the 2.5% imiquimod group and highest in the placebo group in the PPpopulation. At EOS, the mean change and mean percent change fromBaseline in EGW count was significantly greater in the active treatmentgroups compared with placebo, however the difference between the activetreatment groups was not statistically significant.

In the female subgroup only, the mean change and mean percent changefrom Baseline in EGW count at EOS was significantly lower in both activetreatment groups compared with placebo, and there was no significantdifference between the active treatment groups. In males, the meanchange and mean percent change was lower in both active treatment groupscompared with placebo; the difference in mean change was significantonly for the 2.5% imiquimod group, but the difference in mean percentchange was significant for both the 3.75% and 2.5% imiquimod groups.

The mean percent decrease from Baseline in wart count in the 2 activetreatment groups was consistently larger than placebo. The differencesbetween the active treatment groups and placebo were statisticallysignificant at all post-Baseline time points after Week 4 with theexception of the 2.5% imiquimod group at Week 12, The differencesbetween the 3.75% imiquimod and 2.5% imiquimod groups were notstatistically significant at any analysis time point.

Time to Complete Clearance

Summaries of the time to complete clearance are shown in Table 82 below.

TABLE 82 Time to Clearance (days) for the ITT population Imiquimod Cream3.75% 2.5% Placebo (N = 204) (N = 202) (N = 105) All Subjects(Kaplan-Meier) N 204 202 105 1^(st) Quartile 71.0 101.0 >57 Median timeto complete clearance, 123.0 ≥101 ≥112.0 including all subjects, days Pvalue vs Placebo <0.001 <0.001 — P value vs 2.5% imiquimod cream 0.474 —Only Subjects Who Attained Clearance N 60 50 9 1^(st) Quartile 47.0 43.034.0 Median time to complete clearance, 60.0 63.0 71.0 including onlysubjects who attained clearance, days 3^(rd) Quartile 81.5 100.0 91.0 Pvalues are from the log rank test comparing survival curves in theKaplan-Meier framework, taking 2 treatment groups at a time.

Although the median time to complete clearance for the ITT treatmentgroup was not reached, the median time to complete clearance in the ITTpopulation was statistically significantly shorter in the 2 activetreatment groups compared with placebo (P≤0.001 using the log-ranktest). The difference between the 2 imiquimod treatment groups was notstatistically significant (P=0.474).

For those subjects who attained complete clearance, the median time tocomplete clearance was 60 days in the 3.75% imiquimod group, 63 days inthe 2.75% imiquimod group, and 71 days in the placebo group.

Results in the PP population were similar to those in the ITTpopulation. Among the subset of subjects who achieved complete clearancein the PP population, the median time to clearance was 64 days in the3.75% imiquimod group, 63 days in the 2.5% imiquimod group, and 71 daysin the placebo group.

Complete clearance was achieved more rapidly in female subjects comparedwith males in both the ITT and PP populations.

Sustained Complete Clearance Rate at Week 12 of the Follow-Up forRecurrence Period

The numbers of subjects who remained clear in the follow-up period orwho had a recurrence of EGW are presented in Table 83 below.

TABLE 83 Wart Recurrence Rate-Follow-up for Recurrence Population (LOCF)Imiquimod Cream 3.75% 2.5% Placebo (N = 5) (N = 43) (N = 7) RecurrenceFollow-up-Week 12 Subjects who remained 34/53 (64.2) 29/43 (67.4) 7/7(100.0) clear^(a), n/N (%) Subjects who had a 10/53 (18.9)  7/43 (16.3)0 recurrence, n/N (%) Missed at Week 12 Visit  9/53 (17.0)  7/43 (16.3)0/7 (0.0) 95% Confidence interval 9.4, 32.0 6.8, 30.7 — ^(a)Includesthose who had a visit within window with no warts

Thirty-four subjects (64.2%) in the 3.75% imiquimod group, 29 subjects(67.4%) in the 2.5% imiquimod group, and 7 subjects (100%) in theplacebo group achieved complete clearance at EOS that was sustainedthroughout the 12-week follow-up period. Data were missing for 9subjects (17.0%) in the 3.75% imiquimod group and 7 subjects (16.3%) inthe 2.5% imiquimod group, so their recurrence status was not known, butat least 18.9% of the 3.75% imiquimod group and 16.3% of the 2.5%imiquimod group in the follow-up for recurrence population are known tohave shown recurrence of EGW within 12 weeks of the initial clearance.

Statistical/Analytical Issues

Adjustments for Covariates

The primary efficacy analysis was based on a CMH test, stratified bygender and analysis site. Secondary analyses were performed in a numberof subgroups. No other adjustments for covariates were planned.

Handling of Dropouts or Missing Data

For the primary ITT analysis, missing observations due to earlydiscontinuation were imputed using the LOCF. Screening data were carriedforward if no baseline data existed for the subject. Baseline data werecarried forward if no post-baseline data existed for the subject.Additional analyses of the primary efficacy variable were performed inwhich (1) all missing observations were considered as failures and (2)using only observed cases, without imputations. The results of theseadditional analyses are presented in the Table 84 below.

TABLE 84 Proportion of Subjects with Complete Clearance at End of Study(Sensitivity and Supporting Analyses)-ITT Population Imiquimod Cream3.75% 2.5% Placebo (N = 204) (N = 202) (N = 105) ITT Population (allsubjects with missing data were counted as failures) n/N^(a) (%) 60/204(29.4) 51/202 (25.2) 9/105 (8.6) 95% CI 23.3, 36.2 19.4, 31.8 4.0, 15.6P value vs Placebo <0.001** <0.001**   — P value vs 2.5% Imiquimod  0.231  — Cream ITT Population (observed cases) n/N^(a) (%) 60/204(29.4) 50/202 (24.8) 9/105 (8.6) 95% CI 23.3, 36.2 19.0, 31.8 4.0, 15.6P value vs Placebo <0.001** 0.001** — P value vs 2.5% Imiquimod   0.231 — Cream 95% CI = 95% confidence interval ^(a)n/N = number of subjectswith complete clearance at end of study divided by the number ofsubjects analyzed. P values are from Cochran-Mantel-Haenszel test,stratified by gender and analysis site, taking 2 treatment groups at atime. P-values marked with ** are statistically significant usingHochberg's modified Bonferroni procedure. Confidence intervals werecalculated using the exact binomial distribution.

Results of these additional analyses are identical to those obtainedbased upon LOCF for all treatment groups.

Multicenter Studies

In order to obtain at least 6 subjects per site per active treatmentgroup, investigational sites yielding fewer than 15 subjects werecombined in order of geographic proximity. The exact composition ofthese “analysis sites” was determined and documented prior to breakingthe study blind. The stratification for CMH analyses was based on theanalysis sites, not on the actual investigational sites.

Multiple Comparison/Multiplicity

The primary efficacy endpoint, complete clearance rate at the End ofStudy, was analyzed using Cochran-Mantel-Haenszel (CMH) statistics,stratifying on gender and site. As mentioned above, all pairwisecomparisons of active treatment versus placebo were made usingHochberg's modified Bonferroni procedure. If either test was significantat a 0.025 level of significance, then that test was consideredsignificant. Otherwise, if both tests were significant at 0.05, thenboth tests were considered significant. The 3.75% and 2.5% treatmentgroups were compared to each other at the 0.05 level of significance ifat least one of these treatment groups was found to be different thanthe placebo using the Hochberg's test.

The 4 secondary efficacy variables were to be tested hierarchicallyusing Hochberg's modified Bonferroni procedure to conserve Type 1 error.First, only if the primary endpoint showed statistical significant couldthe first secondary efficacy variable be tested. If the prior secondaryefficacy variable showed statistical significance then the nextsecondary efficacy variable could be tested, etc.

Use of an “Efficacy Subset” of Subjects

Efficacy variables were analyzed for a Per Protocol (PP) subset ofsubjects. The PP population included all subjects in the ITT populationwho had no major protocol violations: 144 subjects in the 3.75%imiquimod treatment group, 144 subjects in the 2.5% imiquimod treatmentgroup, and 81 subjects in the placebo group. The demographic andbaseline characteristics in the PP population were similar to those inthe population, although the mean total wart area decreased in the 3.75%imiquimod group.

In the analysis of the primary efficacy variable, the results in the PPpopulation were similar to those in the ITT population. The proportionof subjects with complete clearance at Week 16/EOS was statisticallysignificantly greater in the active treatment groups compared withplacebo.

Results in the PP population for the other efficacy variables were alsosimilar to those from the ITT population.

Examination of Subgroups

The primary efficacy variable was summarized without statistical testingby, investigator site, by analysis site, by investigator medicalspecialty, by gender, by age subgroup, by race subgroup, by baseline EGWcount subgroup, by baseline wart areas, by anatomic locations (inguinal,perineal, perianal, glans penis, penis shaft, scrotum, foreskin, orvulva), by number of anatomic locations affected by EGW (ie, onelocation versus multiple), by whether first EGW episode, by durationfrom first diagnosis of EGW, by rest periods (yes or no), and byprevious treatment with imiquimod (yes or no).

In general, the complete clearance rates increased in a dose-dependentmanner regardless of subgroup. The most striking subgroup effect wasobserved in the analysis by gender. Complete clearance at EOS wasattained by 17.0%, 15.3%, and 4.1% of male subjects, and by 38.8%,31.6%, and 12.5% of females in the 3.75%, 2.5%, and placebo groups,respectively.

The complete clearance tended to be higher in the following subgroups:

-   -   Females;    -   Lower baseline wart count (≤7 compared with >7);    -   Baseline wart area ≤70 mm²;    -   Subjects with baseline warts in the perianal, perineal and glans        penis;    -   Subjects who took a rest period (noted in the imiquimod groups        but not placebo);    -   No previous imiquimod treatment (noted in the imiquimod groups        but not placebo).

In the 3.75% imiquimod group, the complete clearance rate was higher inolder subjects (>35 years) compared with younger subjects.

When analyzed by analysis site or investigative site subgroups, thecomplete clearance rate was highest in the 3.75% imiquimod group at12/24 analysis sites and 17/43 investigative sites.

When analyzed by investigator site specialty subgroups, the highestoverall complete clearance rates were observed at sites specializing ingynecology (sites where more females were enrolled) or infectiousdisease. At sites specializing in dermatology and urology, the clearancerates decreased with increasing imiquimod dose. Few subjects in anytreatment group attained complete clearance at sites specializing indermatology or urology (sites at which only male subjects were enrolled)or infectious disease.

Additional Analysis by Gender

Additional analyses of the data were performed to explore the possibleeffect of gender on efficacy. Of the 511 subjects randomized into thetrial, 222 (43.4%) were male and 289 (56.6%) were female. Similarpercentages of males and females completed the evaluation period. Lostto follow-up and subject's request were the most common reasons forstudy discontinuation in both genders. The time to loss of follow-up wassimilar in the active treatment groups for both genders. However, inmales, the highest percentage of subjects lost to follow-up were in the3.75% imiquimod group, and in females, the highest percentage ofsubjects lost to follow-up were in the 2.5% imiquimod group.

As in the overall population, the response with 3.75% imiquimod creamwas significantly superior to that with placebo in both genders. Thecomplete clearance rates were consistently higher in females comparedwith males in all treatment groups for both the ITT and PP populations,including the sensitivity and supporting analyses of the ITT population.

A summary of complete clearance of all anatomic sites at EOS by baselineinvolvement of anatomic locations is presented in Table 85 below. Ofnote, a majority of subjects of each gender had involvement of more thanone anatomic site at baseline.

TABLE 85 Complete Clearance at End of Study by Baseline AnatomicLocation,-ITT Population (LOCF) Imiquimod Cream 3.75% 2.5% PlaceboBaseline anatomic location (N = 204) (N = 202) (N = 105) Bothgenders-n/N (%)^(a) Inguinal 3/35 (8.6) 7/36 (19.4) 1/23 (4.3) Perinea]26/67 (38.8) 18/61 (29.5) 2/32 (6.3) Perianal 28/61 (45.9) 19/57 (33.3)4/31 (12.9) Males-n/N (%)^(a) Inguinal 1/24 (4.2) 2/17 (11.8) 1/19 (5.3)Perinea] 1/6 (16.7) 1/8 (12.5) 0/3 (0.0) Perianal 3/8 (37.5) 0/6 (0.0)0/5 (0.0) Glans Penis 4/9 (44.4) 3/11 (27.3) 0/5 (0.0) Penis Shaft 10/71(14.1) 12/76 (15.8) 2/39 (5.1) Scrotum 0/19 (0.0) 1/16 (6.3) 0/14 (0.0)Foreskin — 0/2 (0.0) 0/2 (0.0) Females-n/N (%)^(a) Inguinal 2/11 (18.2)5/19 (263) 0/4 (0.0) Perineal 25/61 (41.0) 17/53 (32.1) 2/29 (6.9)Perianal 25/53 (47.2) 19/51 (37.3) 4/26 (15.4) Vulva 31/86 (36.0) 22/78(28.2) 5/31 (16.1) ^(a)Subjects with complete clearance are included inthe numerator.

In the anatomic areas common to both genders, perineal and perianalinvolvements were relatively common in females: few males had baselinedisease in those areas. Females with perineal or perianal EGW atBaseline demonstrated relatively high rates of complete clearance atEOS. The third most common anatomic site, the inguinal area, was presentin more males in the 3.75% imiquimod and placebo groups but comparablein both genders in the 2.5% imiquimod group. Females in the activetreatment groups had a higher rate of complete clearance than males. Thelowest clearance rates occurred in subjects with inguinal areainvolvement (at Baseline) in all treatment groups. The completeclearance rates at EOS by baseline anatomic location for each gender areshown in Table 85.

The anatomic areas most commonly affected with EGW at Baseline in maleswere the penis shaft, inguinal, and scrotum area. The complete clearancerates were highest in the subjects whose EGW at Baseline was in theglans penis and perianal area for the 3.75% imiquimod group comparedwith the 2.5% imiquimod group and placebo. In females, the vulva,perineal, and perianal areas were the areas most commonly affected withEGW at Baseline. The complete clearance rates were highest with 3.75%imiquimod for all baseline anatomic areas with the exception of theinguinal area in females.

In both genders, complete clearance rates were higher in subjects whotook a rest period from imiquimod treatment compared with those who didnot take a rest period. The complete clearance rates in males andfemales were higher for subjects >35 years of age than in youngersubjects. Females with a first EGW diagnosis within one year had higherclearance rates than those with a longer EGW history. Males with a firstEGW diagnosis after one year had higher clearance rates than those witha shorter EGW history.

Exploratory Analysis of Anatomic Specific Complete Clearance

In this study, subjects applied study medication to individual warts invarious anatomic areas identified at Baseline. Some subjects developednew warts during the study. These new warts may have appeared withinanatomic areas already displaying EGW at Baseline and/or these new wartsmay have appeared in ‘new’ anatomic areas that had not been exposed tostudy medication at initiation of treatment. New warts were treated withstudy medication when they appeared, but received less than a fullcourse of treatment, because treatment was not extended beyond 8 weeksfrom randomization.

An exploratory analysis of complete clearance within the specificanatomic areas affected with EGW at Baseline was performed for theoverall ITT population and by gender.

Drug Dose, Drug Concentration, and Relationships to Response

This study examined the efficacy of 2.5% imiquimod cream and 3.75%imiquimod cream, that was applied once daily for a maximum of 8 weeks.Subjects self-applied a maximum of 1 packet (250 mg) of study drug perapplication. No sample collection for pharmacokinetic determinations wasplanned in this study; therefore, no analysis of drug concentration wasdone.

A dose response was observed in this study. The 3.75% imiquimod creamconsistently demonstrated higher efficacy rates compared with the 2.5%imiquimod cream for all primary and secondary efficacy measures, in boththe ITT and PP populations. The difference between the 2 activetreatment groups was not statistically significant for primary efficacyanalysis, secondary and tertiary efficacy variables.

Efficacy Conclusions

The investigational products 3.75% imiquimod cream and 2.5% imiquimodcream met the criteria for efficacy as defined in this protocol.

-   -   For the primary endpoint (the rate of complete clearance of EGW        at Week 16/EOS), results with 3.75% imiquimod cream and 2.5%        imiquimod cream were statistically significantly superior to        results with the placebo cream (P<0.001). This effect was        observed in both the ITT and PP populations. In the ITT        population, the complete clearance rates were 29.4% and 24.8%,        respectively, in the 3.75% and 2.5% imiquimod treatment groups,        compared with 8.6% in the placebo group. Results in the 3.75%        imiquimod group were numerically but not statistically higher        than in the 2.5% imiquimod group.    -   The complete clearance rate at end of treatment (EOT) was        statistically significantly superior with both active treatment        groups compared with placebo overall and in the female subgroup        in both the ITT and PP populations.    -   Over the course of the study, the complete clearance rates were        significantly superior with both active treatment groups        compared with placebo at every analysis time point after Week 8        in both the ITT and PP populations. Clearance rates were higher        in the 3.75% imiquimod group than in the 2.5% imiquimod group        however the difference was not statistically significant at any        time point during the evaluation period.    -   The partial (≥75%) clearance rate in both active treatment        groups was statistically significantly superior to the placebo        cream at Week 16/EOS for the ITT population and PP population        (overall and in both genders). Results were significantly higher        for the active treatment groups at all analysis time points        after Week 4 for the ITT and PP populations.    -   Over the course of the study, the partial (≥75%) clearance rates        were significantly superior with both active treatment groups at        every analysis time point after Week 6 (ITT population) and Week        8 (PP population). Results were significantly higher for the        3.75% imiquimod vs 2.5% imiquimod at Weeks 6, 12, and 14.    -   The ≥50% clearance rate at EOS was significantly greater in both        active treatment groups compared with placebo in both the ITT        and PP populations, Results were higher in the 3.75% imiquimod        group vs 2.5% imiquimod however the difference was not        statistically significant.    -   Over the course of the study, the ≥50% clearance rates were        significantly superior with both active treatment groups        compared with placebo at every analysis time point after Week 4        in both the ITT and PP populations.    -   The complete and partial clearance rates were consistently        higher in the female subgroup compared with the male subgroup in        all treatment groups. Mean change and percent change from        Baseline in EGW counts were consistently higher in females        compared with males in the active treatment groups.    -   At EOS, the mean percent change from Baseline in wart count with        3.75% imiquimod cream and 2.5% imiquimod cream was statistically        significantly greater than with placebo (P≤0.001) in the ITT and        PP populations.    -   Although the median time to complete clearance for the ITT        treatment group was not reached, the median time to complete        clearance in the ITT population was statistically significantly        shorter in the 2 active treatment groups compared with placebo        (P≤0.001 using the log-rank test). The difference between the 2        imiquimod treatment groups was not statistically significant        (P=0.474). For those subjects who attained complete clearance,        the median time to complete clearance was 60 days in the 3.75%        imiquimod group, 63 days in the 2.75% imiquimod group, and 71        days in the placebo group.    -   Thirty-four of 53 subjects (64.2%) in the 3.75% imiquimod group        remained completely clear of EGW through the 12-week follow-up        period, while 10/53 subjects had wart recurrence. The status is        unknown for 9/53 subjects. Twenty-nine of 43 subjects (67.4%) in        the 2.5% imiquimod group (with 7 missing subjects), and 7 of 7        subjects in the placebo group remained clear through the        follow-up period, Thus, at least 64.2% of the 3.75% imiquimod        group and 67.4% of the 2.5% imiquimod group in the follow-up for        recurrence population are known to have sustained clearance of        all anatomic sites for at least 12 weeks from initial clearance.        Safety Evaluation        Extent of Exposure

An overall summary of study drug exposure for the ITT population ispresented in Table 86 below. One subject was originally randomized tothe 2.5% imiquimod treatment group; however, at Week 2, the subjectincorrectly received a 3.75% imiquimod treatment group kit assigned toanother subject. For the safety analysis the highest dose received(3.75% imiquimod) was used and the subject was considered as part of thesafety population instead of the ITT population.

TABLE 86 Overall Study Drug Exposure-ITT Population Imiquimod Cream3.75% 2.5% Placebo (N = 204) (N = 202) (N = 105) Treatment duration,days^(a)-All subjects N 172 163 89 Mean ± SD 50.0 (15.6) 50.8 (15.3)54.7 (10.9) Median 56 56 56 MM, Max 1, 89 3, 97 13, 73 Total number ofpackets used N 164 159 86 Mean ± SD 43.8 (14.4) 45.1 (14.2) 52.7 (9.5) Median 48 51 56 Min, Max 6, 72 3, 65 13, 76 Number of days treated^(b) N172 163 89 Mean ± SD 43.7 (15.4) 45.6 (15.5) 52.0 (10.9) Median 50 52 55Min, Max 1, 74 3, 92 13, 69 Percent of Treatment Compliance^(c) N 191180 97 Mean ± SD 83.2 (26.7) 86.5 (23.2) 91.1 (20.8) Median 95 96 98 MM,Max  0, 116 13, 118  25, 123 SD—standard deviation, min = minimum, max =maximum. ^(a)Duration of treatment is date of last dose minus date offirst dose plus 1. Last dose is defined as last date on studymedication. ^(b)Days treated is the duration of treatment minus restperiod days and missed doses. ^(c)Based on either packet use complianceor treatment days compliance whichever is greater.

The mean treatment duration, number of study medication packets, andnumber of days were numerically highest in the placebo group comparedwith the 3.75% and 2.5% imiquimod treatment groups.

Based on the available data, on average, the subjects used 43.8 packetsof 3.75% imiquimod, 45.1 packets of 2.5% imiquimod, and 52.7 packets ofplacebo. Mean treatment duration was 50.0 days in the 3.75% imiquimodtreatment group, 50.8 days in the 2.5% imiquimod treatment group, and54.7 days in the placebo group. When rest periods and missed doses weresubtracted, the total number of days treated was reduced to 43.7, 45.6,and 52.0 days in the 3.75% imiquimod, 2.5% imiquimod, and placebogroups, respectively.

The mean number of packets used, number of days treated, and percenttreatment compliance were higher in the males than in females in theactive treatment groups in the ITT and safety populations. Meantreatment duration was higher in males than in females for the 2.5%imiquimod group in the ITT population. There was no difference betweengenders in the placebo group.

Adverse Events (AEs)

Brief Summary of Adverse Events

A summary of the overall incidence of AEs is provided in Table 87 belowfor the safety population.

TABLE 87 Summary of Adverse Events-Safety Population Imiquimod Cream3.75% 2.5% Placebo (N = 205) (N = 201) (N = 105) Subjects with any AE, n(%) 103 (50.2) 101 (50.2) 43 (41.0) Number of AEs 286 227 75 Subjectswith any: Treatment-related^(a) AE, n (%)  40 (19.5)  37 (18.4) 3 (2.9)SAE, n (%)  7 (3.4)  2 (1.0) 1 (1.0) AEs of severe intensity, n (%) 15(7.3) 10 (5.0) 4 (3.8) AE leading to study  3 (1.5)  5 (2.5) 0discontinuation, n (%) AE—adverse event, SAE—serious adverse event^(a)Includes “Probably related” and “Related” AEs. Counts reflectnumbers of subjects in each treatment group reporting one or moreadverse events that map to the MedDRA system organ class. A subject maybe counted once only in each row of the table. A treatment-emergent AEis an AE that began or worsened in severity after Day I and no more than30 days after the last application of study drug. Subject 03/012 in the2.5% imiquimod group, who discontinued from the study at the subject'srequest (CRF page 31) was also recorded as discontinued from the studydue to an adverse event.

The number of subjects who experienced any AE (including those notconsidered treatment emergent) was similar in the active treatmentgroups (103 [50.2%] and 101 [50.2%] in the 3.75% and 2.5% imiquimodgroups, respectively) and lower in the placebo group (43, [41.0%]). Thenumber of subjects with AEs considered treatment-related or severe inintensity was similar in the active treatment groups and lower in theplacebo group. Seven (3.4%) of subjects in the 3.75% imiquimod groupexperienced an SAE. The number of subjects with an SAE or who withdrewfrom the study due to an AE was low in the other 2 treatment groups.

An overall summary of the incidence of treatment-emergent AEs isprovided in Table 88 below.

TABLE 88 Summary of Treatment-Emergent Adverse Events-Safety PopulationImiquimod Cream 3.75% 2.5% Placebo (N = 205) (N = 201) (N = 105)Subjects with any AE, n (%) 91 (44.4) 82 (40.8) 34 (32.4) Number of AEs216 167 51 Subjects with any: Treatment-related^(a) AE, n (%) 40 (19.5)37 (18.4) 3 (2.9) Application site AE, n (%) 35 (17.1) 33 (16.4) 3 (2.9)SAE, n (%) 6 (2.9) 2 (1.0) 1 (1.0) AEs of severe intensity, n (%) 14(6.8)  9 (4.5) 3 (2.9) AE leading to study 3 (1.5) 5 (2.5) 0discontinuation, n (%) AE = adverse event, SAE = serious adverse event^(a)Includes “Probably related” and “Related” AEs. Counts reflectnumbers of subjects in each treatment group reporting one or moreadverse events that map to the MedDRA system organ class. A subject maybe counted once only in each row of the table. A treatment-emergent AEis an AE that began or worsened in severity after Day f and no more than30 days after the last application of study drug.

The number of subjects with treatment-emergent AEs was similar in theactive treatment groups (91 [44.4%] and 82 [40.8%] in the 3.75% and 2.5%imiquimod groups, respectively) and lower in the placebo group (34,[32.4%]). The number of subjects with AEs considered treatment-emergentor severe in intensity was similar in the active treatment groups andlower in the placebo group. A higher percentage of subjects in theactive treatment groups had application site reactions compared withplacebo. The number of subjects with an SAE or who withdrew from thestudy due to an AE was relatively low in all treatment groups.

Most Frequent Adverse Events

A treatment-emergent AE was defined as an AE that began or worsened inseverity after the first application of the study drug and no more than30 days after the last application of the study drug. The incidence ofthe most commonly-occurring treatment-emergent AEs is presented bypreferred term in Table 89 below.

TABLE 89 Number (%) of Subjects with Most Frequent TreatmentEmergentAdverse Events (≥1% in any active treatment group)-Safety PopulationImiquimod Cream 3.75% 2.5% Placebo (N = 205) (N = 201) (N = 105)Subjects with any AE, n (%) 91 (44.4) 82 (40.8) 34 (32.4) Applicationsite pain 17 (8.3)  8 (4.0) 0 Application site pniritus 8 (3.9) 14(7.0)  1 (1.0) Application site irritation 12 (5.9)  8 (4.0) 1 (1.0)Nasopharyngitis 4 (2.0) 7 (3.5) 6 (5.7) Upper respiratory tractinfection 5 (2.4) 4 (2.0) 2 (1.9) Urinary tract infection 4 (2.0) 3(1.5) 2 (1.9) Vaginal candidiasis 1 (0.5) 7 (3.5) 1 (1.0) Nasalcongestion 2 (1.0) 5 (2.5) 1 (1.0) Headache 3 (1.5) 3 (1.5) 1 (1.0)Pruritus genital 4 (2.0) 2 (1.0) 1 (1.0) Scrotal erythema 2 (1.0) 5(2.5) 0 Influenza 1 (0.5) 3 (1.5) 2 (19) Application site rash 2 (1.0) 3(1.5) 0 Application site ulcer 2 (1.0) 3 (1.5) 0 Nausea 3 (1.5) 1 (0.5)1 (1.0) Rash 3 (1.5) 1 (0.5) 1 (1.0) Scrotal ulcer 2 (1.0) 3 (1.5) 0Sinusitis 3 (1.5) 0 2 (1.9) Application site infection 1 (0.5) 3 (1.5) 0Application site vesicles 3 (1.5) 1 (0.5) 0 Sinus congestion 3 (1.5) 1(0.5) 0 Anxiety 3 (15)  0 0 Influenza like illness 0 3 (1.5) 0Musculoskeletal pain 3 (1.5) 0 0 Scrota/pain 3 (1.5) 0 0 AE = adverseevent Counts reflect numbers of subjects in each treatment groupreporting one or more adverse events that map to the MedDRA system organclass. A subject may be counted once only in each row of the table. Atreatment-emergent AE is an AE that began or worsened in severity afterthe first application of the study drug and no more than 30 days afterthe last application of the study drug.

The AE reported with the greatest overall incidence was application sitepain, reported in 8.3% of subjects in the 3.75% imiquimod group, 4.0% ofsubjects in the 2.5% imiquimod group, and 0.0% of subjects in theplacebo group.

Application site pruritus occurred with a higher frequency in the 2.5%imiquimod group (7.0%) compared with the 3.75% imiquimod group (3.9%)and placebo 0.0% groups. Nasopharyngitis occurred with a higherfrequency in the placebo group (5.7%) compared with the 3.75% imiquimodgroup (2.0%), and 2.5% imiquimod group (3.5%). With these exceptions,the incidence of the individual AEs was similar in the 2 activetreatment groups and lower in the placebo group.

Flu-like symptoms and certain other systemic effects have been reportedwith 5% imiquimod treatment. The incidence of these AEs was very low inthe current study. These events were reported in this study in the 3.75%imiquimod, 2.5% imiquimod, and placebo groups, respectively, as follows:

-   -   nausea was reported in 3 (1.5%), 1 (0.5%), and 1 (0.5%)        subjects;    -   influenza was reported in 1 (0.5%), 3 (1.5%), and 2 (1.9%)        subjects;    -   influenza-like illness was reported in 0, 3 (1.5%), and 0        subjects;    -   myalgia was reported in 1 (0.5%), 1 (0.5%), and 0 subjects;    -   pyrexia was reported in 1 (0.5%), 1 (0.5%), and 0 subjects;    -   chills were reported in 0, 1 (0.5), and 0 subjects.        Adverse Events by System Organ Class

The incidence of AEs is presented by system organ class in Table 90below.

TABLE 90 Number (%) of Subjects with Treatment-Emergent Adverse Eventsby System Organ Class-Safety Population Imiquimod Cream 3.75% 2.5%Placebo (N = 205) (N = 201) (N = 105) General disorders and 42(20.5)37(18.4) 5(4.8) administration site disorders Infections andinfestations 36(17.6) 37(18.4) 20(19.0) Respiratory, thoracic, and11(5.4)  10(5.0)  4(3.8) mediastinal disorders Gastrointestinaldisorders 11(5.4)  6(3.0) 3(2.9) Skin and subcutaneous tissue 11(5.4) 3(1.5) 2(1.9) disorders Reproductive system and breast 10(4.9)  13(6.5) 2(1.9) disorders Musculoskeletal and connective 7(3.4) 4(2.0) 1(1.0)tissue disorders Injury, poisoning, and connective 6(2.9) 3(1.5) 4(3.8)tissue disorders Psychiatric disorders 4(2.0) 1(0.5) 1(1.0) Nervoussystem disorders 3(1.5) 5(2.5) 1(1.0) Investigations 2(1.0) 0 1(1.0)Renal and urinary disorders 2(1.0) 0 1(1.0) Neoplasms benign, malignant,and 2(1.0) 0 0 unspecified (incl cysts and polyps) Immune systemdisorders 1(0.5) 1(0.5) 1(1.0) Surgical and medical procedures 1(0.5)1(0.5) 1(1.0) Endocrine disorders 1(0.5) 0 0 Metabolism and nutritiondisorders 1(0.5) 0 0 Vascular disorders 1(0.5) 0 0 Blood and lymphaticdisorders 0 2(1.0) 0 AE = adverse event Counts reflect numbers ofsubjects in each treatment group reporting one or more AEs that map tothe MedDRA system organ class. A subject was counted only once in eachrow of the table.

System organ classes in which AEs were reported with an incidence of ≥5%in at least one treatment group were general disorders andadministrative site disorders, infections and infestations,gastrointestinal disorders, reproductive system and breast disorders,respiratory, thoracic, and mediastinal disorders, and skin andsubcutaneous tissue disorders.

Adverse Events by Intensity

Most of the AEs were of mild or moderate intensity. Four AEs were ratedas severe in at least 2 subjects in any treatment group:

-   -   application site pruritus, reported in 1 subject (0.5%) in the        3.75% imiquimod treatment group, 2 subjects (1.0%) in the 2.5%        imiquimod treatment group, and 0 subjects in the placebo group;    -   application site irritation, reported in 2 subjects (1.0%) in        the 3.75% imiquimod treatment group, 2 subjects (1.0%) in the        2.5% imiquimod treatment group, and 0 subjects in the placebo        group;    -   application site rash, reported in 2 subjects (1.0%) in the        3.75% imiquimod treatment group, 0 subjects in the 2.5%        imiquimod treatment and placebo groups;    -   scrotal erythema, reported in 2 subjects (1.0%®) in the 3.75%        imiquimod treatment group, 1 subject (0.5%) in the 2.5%        imiquimod treatment group, and 0 subjects in the placebo group.        Adverse Events by Relationship to Treatment

Treatment-emergent AEs are summarized by treatment group andrelationship to study treatment in Table 91 below.

TABLE 91 Number (%) of Subjects with Treatment-Emergent Adverse EventsRelated to Treatment-Safety Population Imiquimod Cream Placebo 3.75%2.5% (N = (N = 205) (N = 201) 105) Subjects with any treatment-related40 (19.5) 37 (18.4) 3 (2.9) AE, n (%) Subjects with anytreatment-related: SAE, n (%) 0 0 0 AE of severe intensity, n (%) 9(4.4) 9 (4.5) 1 (1.0) AE leading to study drug 1 (0.5) 3 (1.5) 0discontinuation, n (%) Application site pain 16 (7.8)  8 (4.0) 0Application site pruritus 7 (3.4) 14 (7.0)  1 (1.0) Application siteirritation 11 (5.4)  8 (4.0) 1 (1.0) Application site rash 2 (1.0) 3(1.5) 0 Application site ulcer 2 (1.0) 3 (1.5) 0 Application sitebleeding 2 (1.0) 1 (0.5) 1 (1.0) Application site vesicles 3 (1.5) 1(0.5) 0 Secretion discharge 2 (1.0) 2 (1.0) 0 Application site reactionI (0.5) 2 (1.0) 0 Application site dermatitis 1 (0.5) 1 (0.5) 0Application site discharge 1 (0.5) 1 (0.5) 0 Application site erythema 02 (1.0) 0 Application site erosion 0 1 (0.5) 0 Application siteparaesthesia 0 0 1 (1.0) Application site swelling 1 (0.5) 0 0 Scrotalerythema 2 (1.0) 4 (2.0) 0 Scrotal ulcer 2 (1.0) 3 (1.5) 0 Scrotaloedema 2 (1.0) 2 (1.0) 0 Pruritus genital 2 (1.0) 1 (0.5) 0 Scrotal pain3 (1.5) 0 0 Genital rash 0 1 (0.5) 0 Pelvic pain 0 1 (0.5) 0 Penisdisorder 0 1 (0.5) 0 Prostatitis 1 (0.5) 0 0 Scrotal irritation 1 (0.5)0 0 Vulval disorder 0 1 (0.5) 0 Vulval ulceration 0 1 (0.5) 0Vulvovaginal pruritus 1 (0.5) 0 0 Application site infection 1 (0.5) 3(1.5) 0

TABLE 91 Number (%) of Subjects with Treatment-Emergent Adverse EventsRelated to Treatment-Safety Population Imiquimod Cream 3.75% 2.5%Placebo (N = 205)5 (N = 201) (N = 105) Application site cellulitis 1(0.5) 0 0 Application site pustules 0 1 (0.5) 0 Cellulitis 0 1 (0.5) 0Folliculitis 0 1 (0.5) 0 Fungal infection 1 (0.5) 0 0 Influenza 1 (0.5)0 0 Scrotal infection 1 (0.5) 0 0 Staphylococcal abscess 0 1 (0.5) 0Haemorrhoidal haemorrhage 1 (0.5) 0 0 Haemorrhoids 0 1 (0.5) 0 Nausea 01 (0.5) 0 Groin pain 0 1 (0.5) 0 Myalgia 1 (0.5) 0 0 Pain in extremity 01 (0.5) 0 Rash 1 (0.5) 0 0 Scab 0 1 (0.5) 0 Skin exfoliation 1 (0.5) 0 0Lymph node pain 0 1 (0.5) 0 Burning sensation 0 1.(0.5) 0 Dysuria 1(0.5) 0 0 AE = adverse event Counts reflect numbers of subjects in eachtreatment group reporting one or more AEs that map to the MedDRA systemorgan class. A subject was counted only once in each row of the table.Treatment-related includes Probably Related and Related.

Adverse events considered to be treatment-related were reported in 40subjects (19.5%) in the 3.75% imiquimod treatment group, 37 (18.4%) inthe 2.5% imiquimod treatment group, and 3 (2.9%) in the placebo group.The most frequently reported treatment-related AEs were application sitepain and application site pruritus. Application site AEs were the mostfrequently reported treatment-related AEs followed by AEs involving thescrotum. Application site pruritus, application site irritation,application site bleeding and paraesthesia, each in 1 subject (1.0%),were the only treatment-related AEs reported in the placebo group.

Treatment-related AEs of severe intensity were reported by 9 subjects inthe 3.75% imiquimod group, 9 subjects in the 2.5% imiquimod group, and 1subject in the placebo group. The majority of the AEs were applicationsite reactions and all resolved without sequelae.

Adverse Events by Subgroup

Treatment-emergent AEs were analyzed by gender, by age, by number ofanatomic areas affected by EGW, and by baseline wart count. As in theoverall population, application site reactions were the mostcommonly-reported AEs and treatment-related AEs in all subgroups for alltreatment groups.

Adverse Events by Gender

Summaries of the analysis by gender are provided in Table 92 below.

TABLE 92 Treatment-emergent Adverse Events by Gender-Safety PopulationMale Female 3.75% 2.5% 3.75% 2.5% Imiquimod Imiquimod Placebo ImiquimodImiquimod Placebo n = 88 n = 85 n = 49 n = 117 n = 116 n = 56 Subjectswith any AE, n (%) 37 (42.0) 28 (32.9)  8 (16.3) 54 (46.2) 54 (46.6) 26(46.4) Number of AEs 104 60 11 112 107 40 Number (%) of subjects with:Any Treatment-related AE 16 (18.2) 13 (15.3) 0 (0.0) 24 (20.5) 24 (20.7)3 (5.4) Any SAE 2 (2.3) I. (1.2) 0 (0.0) 4 (3.4) 1 (0.9) I (1.8) AnySevere AE 10 (11.4) 2 (2.4) 0 (0.0) 4 (3.4) 7 (6.0) 3 (5.4) Any AEleading to Study 1 (1.1) 2 (2.4) 0 (0.0) 2 (1.7) 3 (2.6) 0 (0.0)Discontinuation Any Application site 14 (15.9)  9 (10.6) 0 (0.0) 21(17.9) 24 (20.7) 3 (5.4) Reaction

The overall incidence of AEs was higher in females than in males in alltreatment groups. Treatment-related AEs and SAEs were reported in ahigher percentage of females than in males in the 3.75% imiquimod andplacebo treatment groups but not in the 2.5% imiquimod group. Severe AEswere reported in a higher percentage of females in the 2.5% imiquimodand placebo groups, but not in the 3.75% imiquimod group. The incidenceof SAEs and AEs leading to study discontinuation was low in alltreatment groups regardless of gender. Application site reactions werethe most commonly reported AEs in the 2 imiquimod treatment groups.Severe AEs and application site reactions were each reported in 3 femalesubjects (5.4%) in the placebo group.

Adverse Events by Age:

As in the overall population, application site reactions were the mostcommonly-reported treatment-emergent AEs in both age groups for the 2imiquimod treatment groups.

In the active treatment groups, the incidence of treatment-emergent AEswas similar in younger (≤35 years) and older (>35 years) subjects withineach treatment group. Treatment-emergent AEs were reported in 45.1%,40.8%, and 31.8%, respectively, of younger subjects in the 3.75%imiquimod, 2.5% imiquimod, and placebo groups compared with 43.1%,40.8%, and 33.3%, respectively, of the older subjects in the 3.75%imiquimod, 2.5% imiquimod, and placebo groups.

In the active treatment groups, the incidence of treatment-related AEsand application site reactions was slightly higher in younger subjectsthan in older subjects; however, within each age subgroup, there waslittle difference between the active treatments. Few treatment-relatedAEs or application site reactions were reported in subjects in eitherage subgroup who received placebo.

Adverse Events by Number of Anatomic Areas:

As in the overall population, the most commonly-reportedtreatment-emergent AEs and treatment-related AEs in both subgroups forall treatment groups were application site reactions.

In the 2 active treatment groups, similar percentages of subjects in thesingle-area and multiple-area subgroups reported a treatment-emergentAE. In the placebo group, subjects in the multiple-area subgroupreported a higher percentage of treatment-emergent AEs than those in thesingle-area subgroup (36.5% versus 28.3%, respectively). Fortreatment-related AEs and application site reactions, there was littledifference in AE incidence between the subgroups in any of the treatmentgroups.

Adverse Events by Baseline Wart Count:

In the subjects with 7 or fewer warts at Baseline, the incidence of AEswas 43.9%, 39.5%, and 32.8%, respectively, in the 3.75% imiquimod, 2.5%imiquimod, and placebo groups, whereas in subjects with more than 7warts at. Baseline, the incidence of AEs was 45.1%, 42.9%, and 31.6%,respectively, in the 3.75% imiquimod, 2.5% imiquimod, and placebogroups.

In the subjects with 7 or fewer warts at Baseline, the incidence oftreatment-related AEs was 19.5%, 16.9%, and 4,5%, respectively, in the3.75% imiquimod, 2.5% imiquimod, and placebo groups, whereas in subjectswith more than 7 warts at Baseline, the incidence of treatment-relatedAEs was 19.5%, 20.8%, and 0%, respectively, in the 3.75% imiquimod, 2.5%imiquimod, and placebo groups.

There was little difference in the incidence of treatment-emergent AEs,treatment-related AEs, and application site reactions between thesubgroups in any of the active treatment groups. In the placebo group,subjects with 7 or fewer warts had a higher incidence of applicationsite reactions than subjects with more than 7 warts.

Local Skin Reactions

Local skin reactions were assessed by the investigator at each visitincluding Baseline (pretreatment). At Baseline, 5.4%®, 6.0%, and 8.6% ofsubjects in the 3.75% imiquimod, 2.5% imiquimod, and placebo groups,respectively, had at least one LSR reaction (LSR intensity score ≥0).The most intense post-Baseline LSRs (ie, those with the highestintensity rating) in the treatment area that were assessed by theinvestigator over the course of the study are summarized in the Tablebelow (Table 93). The potential maximum sum of LSR scores was 18 (sixtypes of LSRs each with maximum potential score of 3).

TABLE 93 Frequency Distribution of Most Intense Post-baseline Local SkinReactions in the Treatment Area-Safety Population Number (%) of SubjectsImiquimod Type of 3.75% 2.5% Placebo Reaction Intensity (N = 205) (N =201) (N = 105) Erythema N 189 (100)  180 (100)  98 (100)  0 = None  50(26.5)  64 (35.6) 67 (68.4) 1 = Faint to mild  49 (25.9)  49 (27.2) 19(19.4) redness 2 = Moderate  71 (37.6)  47 (26.1) 11 (11.2) redness 3 =Intense redness  19 (10.1)  20 (11.1) 1 (1.0) >0 (any reaction) 139(73.5) 116 (64.4) 31 (31.6) Mean score (SD) 1.31 (0.97)  1.13 (1.02) 0.45 (0.73) Edema N 189 (100)  180 (100)  98 (100)  0 = None 108 (57.1)111 (61.7) 89 (90.8) 1 = Mild visible/  59 (31.2)  47 (26.1) 8 (8.2)barely palpable swelling/induration 2 = Easily palpable  19 (10.1) 16(8.9) 1 (1.0) 3 = Gross swelling/  3 (1.6)  6 (3.3) 0 induration >0 (anyreaction)  81 (42.9)  69 (38.3) 9 (9.2) Mean score (SD) 0.56 (0.74) 0.54 (0.79)  0.10 (0.34) Weeping/ N 189 (100)  180 (100)  98 (100) Exudate 0 = None 124 (65.6) 125 (69.4) 95 (96.9) 1 = Minimal  49 (25.9) 41 (22.8) 3 (3.1) exudate 2 = Moderate 12 (6.3) 12 (6.7) 0 exudate 3 =Heavy exudate  4 (2.1)  2 (1.1) 0 >0 (any reaction)  65 (34.4)  55(30.6) 3 (3.1) Mean score (SD) 0.45 (0.71)  0.39 (0.66)  0.03 (0.17)Flaking/ N 189 (100)  180 (100)  98 (100)  Scaling/ 0 = None 129 (68.3)144 (80.0) 87 (88.8) Dryness 1 = Mild dryness/  52 (27.5)  28 (15.6) 11(11.2) flaking 2 = Moderate  8 (4.2)  6 (3.3) 0 dryness/flaking 3 =Severe 0  2 (1.1) 0 dryness/flaking >0 (any reaction)  60 (31.7)  36(20.0) 11 (11.2) Mean score (SD) 0.36 (0.56)  0.26 (0.57)  0.11 (0.32)Scabbing/ N 189 (100)  180 (100)  98 (100)  Crusting 0 = None 141 (74.6)141 (78.3) 93 (94.9) 1 = Crusting  41 (21.7)  30 (16.7) 5 (5.1) 2 =Serious scab  6 (3.2)  8 (4.4) 0 3 = Eschar  1 (0.5)  1 (0.6) 0 >0 (anyreaction)  48 (25.4)  39 (21.7) 5 (5.1) Mean score 0.30 (0.55)  0.27(0.57)  0.05 (0.22) Erosion/ N 189 (100)  180 (100)  98 (100) Ulceration 0 = None 116 (61.4) 118 (65.6) 92 (93.9) 2 = Erosion  51(27.0)  40 (22.2) 5 (5.1) 3 = Ulceration  22 (11.6)  22 (12.2) 1(1.0) >0 (any reaction)  73 (38.6)  62 (34.4) 6 (6.1) Mean score (SD)0.89 (1.16)  0.81 (1.16)  0.13 (0.53) SD = Standard deviation. Note: Forpurposes of analysis, ‘Erosion’ is categorized as 2 = Moderate, and‘Ulceration’ is categorized as 3 = Severe. Denominator for the mostintense reaction is the number of subjects with at least onepost-baseline assessment.

As displayed in the Table above, the incidence of each type of LSR washigher in the active treatment groups compared with placebo. For eachLSR, the percentage of subjects with any reaction and the mean intensityscore were highest in the 3.75% imiquimod treatment group, somewhatlower in the 2.5% imiquimod group, and lowest in the placebo group. Theincidence of severe LSRs was similar between the active treatment groupswithin each LSR category, and lower in the placebo group.

Erythema was the LSR reported with the greatest frequency and thegreatest mean intensity in all 3 treatment groups. Severe erythema wasreported in 10.1% of subjects in the 3.75% imiquimod group, 11.1% ofsubjects in the 2.5% imiquimod group, and 1.0% of subjects in theplacebo group. The mean intensity score was higher in the activetreatment group (1.31 and 1.13 in the 3.75% and 2.5% imiquimod groups,respectively) compared with placebo.

Edema rated as severe was reported in 1.6% and 3.3% of subjects in the3.75% and 2.5% imiquimod groups, respectively, compared with no subjectsin the placebo group. The mean intensity scores were higher in theactive treatment groups (0.56 and 0.54 in the 3.75% and 2.5% imiquimodgroups, respectively) compared with 0.10 in the placebo group.

For erosion/ulceration severe reactions (ulceration) were reported in11.6% and 12.2% of subjects in the 3.75% and 2.5% imiquimod groups,respectively, compared with 1.0% of subjects in the placebo group. Themean intensity scores were higher in the active treatment groups (0.89and 0.81 in the 3.75% and 2.5% imiquimod groups, respectively) comparedwith 0.13 in the placebo group.

The majority of cases of weeping/exudate, flaking/scaling, andscabbing/crusting were mild in intensity. Few subjects in any treatmentgroup had a reaction considered to be severe.

A summary of subjects who had any post-baseline local skin reaction ispresented in Table 94 below.

TABLE 94 Summary of Subjects Who Had Any Local Skin Reaction During theStudy-Safety Population Number (%) of Subjects Imiquimod Most Intense3.75% 2.5% Placebo Reaction (post-Baseline) (N = 205) (N = 201) (N =105) N 189 180 98 0 = None 41 (21.7)  57 (31.7) 57 (58.2) 1 = Mild 41(21.7)  42 (23.3) 26 (26.5) 2 = Moderate 74 (39.2)  48 (26.7) 13 (133) 3 = Severe 33 (17.5)  33 (18.3) 2 (2.0) >0 (any reaction) 148 (78.3) 123 (68.3) 41 (41.8) Mean score (SD) 1.5 (1.0)   1.3 (1.1)  0.6 (0.8)  SD = Standard deviation. Note: For purposes of analysis, ‘Erosion’ iscategorized as 2 = Moderate, and ‘Ulceration is categorized as 3 =Severe. Denominator for the most intense reaction is the number ofsubjects with at least 1 post-baseline assessment.

As noted for the individual LSRs, the percentage of subjects reportingan LSR at each intensity category was higher in the active treatmentgroup compared with placebo, and was somewhat higher with 3.75%imiquimod than with 2.5% imiquimod. Severe reactions were reported by17.5% of subjects in the 3.75% imiquimod group and 18.3% of subjects inthe 2.5% imiquimod group compared with 2.0% of subjects in the placebogroup. The mean score for the most intense LSR reaction was slightlyhigher in the 3.75% imiquimod group (1.5) than in the 2.5% imiquimodgroup (1.3).

The mean LSR sum score is shown by study week in FIG. 24.

Erythema was the major contributor to the LSR sum score in all treatmentgroups, as determined by visual inspection. In the imiquimod treatmentgroups, the mean LSR sum score peaked at Week 2, decreased slightlyduring the treatment period, and rapidly decreased when treatment wasdiscontinued. Mean LSR scores in the placebo group were highest at Week4 but were considerably lower than those seen with active treatment.

Rest Periods

Summaries of the rest periods for the safety population are presented inTable 95 below.

TABLE 95 Summary of Rest Periods-Safety Population Imiquimod Cream 3.75%2.5% Placebo (N = 205) (N = 201) (N = 105) Subjects requiring restperiod,   67 (32.7)   55 (27.4)   3 (2.9) n/N (%)^(a) P value vs Placebo<0.001 <0.001 NA P value vs 2.5% imiquimod cream 0.234 NA NA No. ofdosing days missed due to rest period^(b) N 67 55 3 Mean (SD) 10.3(8.1)  9.3 (6.7) 6.7 (4.7) Median 7 7 5 P value vs Placebo 0.522 0.526NA P value vs 2.5% cream 0.714 NA NA No. of dosing days prior to thebeginning of the first rest period^(b°) N 67 55 3 Mean (SD) 18.3 (11.5)18.9 (13.7) 25.7 (4.0)  Median 14 14 28 P value vs Placebo 0.151 0.192NA P value vs 2.5% cream 0.924 NA NA No. = number; SD = standarddeviation; NA = not applicable ^(a)P values are fromCochran-Mantel-Haenszel test, stratified by gender and analysis site,taking 2 treatment groups at a time. ^(b)P values are from the WilcoxonRank Sum test, taking 2 treatment groups at a time.

Significantly larger percentages of subjects in the active treatmentgroups compared with placebo took a rest period during the study(P<0.001). There was no significant difference between the activetreatments in the percentage of subjects who took a rest period (32.7%and 27.4% in the 3.75% and 2.5% imiquimod groups, respectively). Therewere no statistically significant differences between the treatmentgroups in the mean duration of rest periods or the mean number of dosingdays prior to the rest periods.

Analysis of Adverse Events

Application site reactions are commonly reported for topically appliedproducts. An additional analysis of these events is presented below.

Application site reactions reported in this study are displayed in Table96 below.

TABLE 96 Number (%) of Subjects with Treatment-Emergent Application SiteAdverse Events-Safety Population Imiquimod Cream 3.75% 2.5% Placebo (N =205) (N = 201) (N = 105) Subjects with any application site 35 (17.1) 33(16.4) 3 (2.9) reaction, n (%) Number of application site reactions 5954 4 Number (%) of subjects with any: Related Application Site Reaction^(a), 33 (16.1) 32 (15.9) 3 (2.9) n (%) Serious Application SiteReaction, 0 0 0 n (%) Severe Application Site Reaction, 6 (2.9) 6 (3.0)1 (1.0) n (%) Application Site Reaction Leading to 1 (0.5) 3 (1.5) 0Study Discontinuation, n (%) General disorders and administration 35(17.1) 32 (15.9) 3 (2.9) site conditions, n (%) Application site pain 17(8.3)  8 (4.0) 0 Application site pruritus 8 (3.9) 14 (7.0)  1 (1.0)Application site irritation 12 (5.9)  8 (4.0) 1 (1.0) Application siterash 2 (1.0) 3 (1.5) 0 Application site ulcer 2 (1.0) 3 (1.5) 0Application site bleeding 2 (1.0) 1 (0.5) 1 (1.0) Application sitevesicles 3 (1.5) 1 (0.5) 0 Application site reaction 1 (0.5) 2 (1.0) 0Application site dermatitis 1 (0.5) 1 (0.5) 0 Application site discharge1 (0.5) 1 (0.5) 0 Application site erythema 0 2 (1.0) 0 Application sitedryness 1 (0.5) 0 0 Application site erosion 0 1 (0.5) 0 Applicationsite hypersensitivity 0 1 (0.5) 0 Application site reaction 1 (0.5) 0 0Application site paraesthesia 0 0 1 (1.0) Application site swelling 1(0.5) 0 0 Infections and infestations, n (%) 2 (1.0) 4 (2.0) 0Application site infection 1 (0.5) 3 (1.5) 0 Application site cellulitis1 (0.5) 0 0 Application site pustules 0 1 (0.5) 0 ^(a) Includes‘Probably related’ and ‘Related’ adverse events. Note: Counts reflectnumbers of subjects in each treatment group reporting 1 or more AEs thatmap to the MedDRA system organ class. A subject may be counted once onlyin each row of the table.

The incidence of application site AEs and treatment-related applicationsite AEs was similar in the 3.75% and 2.5% imiquimod treatment studygroups. Few subjects in any of the treatment groups reported severeapplication site events or application site events that led to studywithdrawal. No serious application site reactions were reported in anystudy group.

Listing of Deaths, Other Serious Adverse Events and Other SignificantAdverse Events

Deaths

There was one death in the study (a 28-year old White male randomized tothe 3.75% imiquimod group). The subject was undergoing treatment for EGWon the glans penis and penis shaft and in the inguinal area. At the timeof the event (gunshot wound to the chest) the subject had applied anunknown number of packets of 3.75% imiquimod cream. The fatal gunshotwound to the chest occurred on Study Day 40. The subject was receivingparacetamol 650 mg po prn and topical Benzamycing 90 g qhs at the timehe was hospitalized.

Other Serious Adverse Events

Serious adverse events are presented in Table 97 below.

TABLE 97 Number (%) of Subjects with Serious Adverse Events- SafetyPopulation Imiquimod Cream 3.75% 2.5% Placebo (N = 205) (N = 201) (N =105) Subjects with any serious adverse 7 (3.4) 2 (1.0) 1 (1.0) event, n(%) Subjects with any treatment- 6 (2.9) 2 (1.0) 1 (1.0) emergent SAE, n(%) Subjects with any treatment- 0 0 0 related SAE, n (%) Seriousadverse events Malignant melanoma 2 (1.0) 0 0 Anxiety 1 (0.5) 0 0Suicidal ideation 0 1 (0.5) 0 Chest pain 1 (0.5) 0 0 Diverticulitis 1(0.5) 0 0 Gun shot wound 1 (0.5) 0 0 Diabetes mellitus inadequatecontrol 1 (0.5) 0 0 Arthritis 0 0 1 (1.0) Dyspnoea 1 (0.5) 0 0 Ovariancystectomy 0 1 (0.5) 0 Gall bladder disorder^(a) 1 (0.5) NA NAPancreatic carcinoma^(a) 1 (0.5) NA NA Ovarian epithelial cancer^(a) 1(0.5) NA NA Bile duct obstruction^(a) 1 (0.5) NA NA Abdominal pain^(a) 1(0.5) NA NA Abdominal distension^(a) 1 (0.5) NA NA Pneumothorax^(a) 1(0.5) NA NA Catheter related infection^(a) 1 (0.5) NA NA Obstructiongastric^(a) 1 (0.5) NA NA Counts reflect numbers of subjects in eachtreatment group reporting one or more adverse events that map to theMedDRA system organ class. A subject was counted only once in each rowof the table. ^(a)Subject 03/014 was diagnosed with cancer duringscreening. All events reported for this subject were classified as nontreatment-emergent SAEs.

Few SAEs were reported during the study. The overall incidence of SAEswas higher in the 3.75% imiquimod group than in the 2.5% imiquimod andplacebo groups. Treatment-emergent SAEs occurred in 6 subjects (2.9%) inthe 3.75% imiquimod group, 2 subjects (1.0%) in the 2.5% imiquimodgroup, and 1 subject (1.0%) in the placebo group. No trends wereevident. No treatment-related SAEs were reported by subjects in any ofthe treatment groups. Two SAEs (anxiety and suicidal ideation) wererecorded as ongoing, 2 SAEs (diabetes and ovarian cystectomy) resolvedwith sequelae, and all other SAEs resolved without sequelae.

Other Significant Adverse Events

Treatment-emergent AEs that led to discontinuation from the study arepresented in Table 98.

TABLE 98 Number (%) of Subjects with Treatment-Emergent Adverse EventsLeading to Study Discontinuation-Safety Population Imiquimod Cream 3.75%2.5% Placebo (N = 205) (N = 201) (N = 105) Subjects with an AE leadingto 3 (1.5) 5 (2.5) 0 study discontinuation, n (%) Subjects with atreatment-related 1 (0.5) 3 (1.5) 0 AE leading to study discontinuation,n (%) Adverse events leading to discontinuation, n (%) Application sitepain 1 (0.5) 2 (1.0) 0 Gunshot wound 1 (0.5) 0 0 Malignant melanomaright breast 1 (0.5) 0 0 Malignant melanoma right lower 1 (0.5) 0lateral extremity Hypersensitivity Application site erythema 0 1 (0.5)Application site irritation 0 1 (0.5) 0 Application site pruritus 0 1(0.5) 0 Scrotal erythema 0 1 (0.5) 0 Scrotal ulcer 0 1 (0.5) 0 Lymphnode pain 0 1 (0.5) 0 Pelvic pain 0 1 (0.5) 0 Groin pain 0 1 (0.5) 0Application site ulcer 0 1 (0.5) 0 Cellulitis 0 1 (0.5) 0 Applicationsite infection 0 1 (0.5) 0 Suicidal ideation 0 1 (0.5) 0 Counts reflectnumbers of subjects in each treatment group reporting one or moreadverse events that map to the MedDRA system organ class. A subject wascounted only once in each row of the table. A treatment-emergent AE isan AE that began or worsened in severity after the first application ofthe study drug and no more than 30 days after the last application ofthe study drug. Treatment-related includes Probably Related and Related.

The incidence of AEs that led to study discontinuation was low in alltreatment groups. The number of subjects with any AE leading to studydiscontinuation was higher in the 2.5% imiquimod group than in the 3.75%imiquimod group. No subjects in the placebo group discontinued the studybecause of AEs. Only 1 subject in the 3.75% imiquimod group and 3subjects in the 2.5% imiquimod group reported treatment-related AEs thatled to study discontinuation. Subject 06/021 (3.75% imiquimod)discontinued the study because of application site pain. In the 2.5%imiquimod treatment group, Subject 04/022 discontinued the study becauseof application site pain, Subject 12/010 discontinued the study becauseof application site erythema, application site irritation, applicationsite pain and application site pruritus, and Subject 18/016 discontinuedthe study because of scrotal erythema and scrotal ulcer in anon-treatment area, lymph node pain, pelvic pain, groin pain, andapplication site ulcer. All (except scrotal erythema and scrotal ulcerin a non-treatment area) were application site reactions. All of theseAEs resolved without sequelae.

Analysis and Discussion of Serious Adverse Events, and Other SignificantAdverse Events

One death (3.75% imiquimod group) occurred among the subjects in thisstudy. The incidence of SAEs was low in this study. No SAE wasconsidered related to study treatment. Few subjects discontinued thestudy as a result of an AE. Treatment-related application site reactionsaccounted for less than half of the AEs leading to study withdrawal.Only two SAEs (anxiety and suicidal ideation) were noted as ongoing and2 SAEs (diabetes and ovarian cystectomy) resolved with sequelae.

Clinical Laboratory Evaluation

For most of the hematological, chemistry, and urinalysis variables, themajority of the subjects were normal at Screening and at EOS. Occasionalshifts from normal at Screening to above or below the limits of thenormal range were observed; however, no dose-response relationship wasevident.

For the clinical chemistry determinations, shifts from normal to highwere most frequently recorded for ALT (15/155 in the 3.75% imiquimodgroup, 11/146 in the 2.5% imiquimod group, and 2/80 in the placebogroup), AST (11/155 in the 3.75% imiquimod group, 4/144 in the 2.5%imiquimod group, and 3/79 in the placebo group), and glucose (8/156 inthe 3.75% imiquimod group, 10/146 in the 2.5% imiquimod group, and 4/79in the placebo group). Low cholesterol was noted in 6/156 in the 3.75%imiquimod group, 8/146 in the 2.5% imiquimod group, and 5/82 in theplacebo group. High cholesterol was also noted in 9/156 in the 3.75%imiquimod group, 6/146 in the 2.5% imiquimod group, and 6/82 in theplacebo group. Shifts from normal to low were most frequently recordedfor cholesterol (9/156 in the 3.75% imiquimod group, 7/146 in the 2.5%imiquimod group, and 3/82 in the placebo group).

In the hematology analyses, shifts from normal to high were mostfrequently reported for neutrophils (5/155 in the 3.75% imiquimod group,7/147 in the 2.5% imiquimod group, and 6/80 in the placebo group).Shifts from normal to low were most frequently reported for WBCs (6/155in the 3.75% imiquimod group, 6/147 in the 2.5% imiquimod group, and4/80 in the placebo group).

The most commonly-reported shift observed in the study was a shift fromnormal to high in urine protein (37/156 in the 3.75% imiquimod group,35/143 in the 2.5% imiquimod group, and 17/79 in the placebo group).However, at screening, 24.4%, 20.3%, and 16.5% in the 3.75% imiquimodgroup, 2.5% imiquimod group, and placebo group, respectively, had highconcentrations of urinary protein. Other findings from urinalysisincluded shifts from normal to high for leukocyte esterase (12/156 inthe 3.75% imiquimod group, 13/143 in the 2.5% imiquimod group, and 2/79in the placebo group) and blood in the urine (11/156 in the 3.75%imiquimod group, 6/143 in the 2.5% imiquimod group, and 2/79 in theplacebo group).

Pregnancies and Outcome

Five women became pregnant during the study, 2 in the 3.75% imiquimodgroup, 2 in the 2.5% imiquimod group, and 1 in the placebo group. All ofthe pregnancies were discovered after the subject had taken her lastdose of study medication. The exposure to study medication was 45packets and unknown of 3.75% imiquimod cream, unknown and 24 packets of2.5% imiquimod cream, and 55 packets of placebo cream. The outcomes ofthe pregnancies are to be determined.

In addition, one subject in the 2.5% group reported that she waspregnant, just after a negative urine test result was reported at theWeek 8 visit. The exposure to study medication was 55 packets.

Safety Conclusions

-   -   Mean exposure to study medication was approximately 44 packets,        45 packets, and 53 packets of study medication in the 3.75%        imiquimod, 2.5% imiquimod, and placebo groups respectively. Mean        treatment duration was similar among the study groups and ranged        from 50.0 days in the 3.75% imiquimod group to 54.7 days in the        placebo group.    -   Treatment-emergent AEs were reported in 44.4%, 40.8%, and 32.4%        of subjects in the 3.75% imiquimod, 2.5% imiquimod, and placebo        groups, respectively. Most AEs were mild or moderate in        intensity. Application site reactions were the most frequently        reported AEs. Adverse events of the system organ classes        “general disorders and administration site conditions” and        “infections and infestations” were the most frequently reported.        Incidences of these events were similar in the active treatment        groups.    -   The incidence of systemic symptoms (ie, flu-like symptoms, etc)        previously noted with 5% imiquimod was low (1%) in this study.    -   Treatment-emergent SAEs were reported in 6 subjects in the 3.75%        imiquimod group, 2 subjects in the 2.5% imiquimod group, and 1        subject in the placebo group. None of the SAEs were considered        treatment-related.    -   Treatment-emergent AEs that led to study discontinuation were        reported in 3 subjects, 5 subjects, and no subjects in the 3.75%        imiquimod, 2.5% imiquimod, and placebo groups, respectively. Of        those TEAEs leading to discontinuation, 4 subjects withdrew from        the study for TEAEs considered treatment-related: 1 subject in        the 3.75% imiquimod group and 3 subjects in the 2.5% imiquimod        group. All (except scrotal erythema and scrotal ulcer in a        non-treatment area) were application site reactions.    -   The incidence of TEAEs and severe AEs was higher in females than        in males across all treatment groups, and the incidence of        application site reactions was higher in females than in males        in the active treatment groups.    -   Adverse events leading to study discontinuation were rare in all        treatment groups regardless of gender.    -   Local skin reactions were reported in 78.3%, 68.3%, and 41.8% of        subjects in the 3.75% imiquimod, 2.5% imiquimod, and placebo        groups, respectively. The incidence and severity of LSRs was        higher in the active treatment groups than in the placebo group.        Erythema was the LSR reported with the greatest frequency and        the greatest mean intensity in all treatment groups. Local skin        reactions were coincident with the treatment period and rapidly        decreased when treatment was concluded. Severe intensity LSRs        were similar in the active groups.    -   Rest periods were taken by 67 subjects (32.7%), 55 subjects        (27.4%), and 3 subjects (2.9%©) in the 3.75% imiquimod, 2.5%        imiquimod, and placebo groups, respectively. The frequency,        duration, and number of dosing days prior to the rest period        were similar in the active treatment group and lower in the        placebo group.    -   There was no evidence of clinically meaningful trends in vital        sign measurements or clinical laboratory measurements. One        subject in the placebo group reported laboratory AEs that were        considered clinically significant, the AEs were considered not        related to treatment.        Discussion and Overall Conclusions        Discussion

In this double-blind, placebo controlled clinical study, 511 subjectswith EGW diagnosed by clinical examination were randomized to receivetreatment with 3.75% imiquimod cream, 2.5% imiquimod cream, or amatching placebo cream. During the evaluation period, subjects appliedstudy medication once daily to the identified treatment area(s) for amaximum of 8 weeks. If the subject did not achieve complete wartclearance by the Week 8 visit (end of treatment [EOT]), the subject wasmonitored for an additional maximum 8 weeks of no treatment. Subjectsdetermined to have achieved complete clearance of all warts at any timeuntil Week 16 (end of study [EOS]) completed procedures for theend-of-study visit and were eligible to immediately enter the follow-upperiod for determination of wart recurrence. During the follow-upperiod, subjects were monitored every 4 weeks for up to 12 weeks oruntil the recurrence of warts. The 3.75% imiquimod cream and 2.5%imiquimod cream demonstrated efficacy and tolerability as compared withplacebo for treatment of EGW. Overall, 71.1% of subjects completed theevaluation period, and the discontinuation rates were similar in alltreatment groups. Compliance with the daily treatment regimen rangedfrom 83.2% in the 3.75% imiquimod group to 91.1% in the placebo group.

Imiquimod has been demonstrated to be a safe and effective treatment forEGW. The dosing regimen for the currently approved product, 5% imiquimodcream, is 3 times per week for up to 16 weeks. Clinical experience hasshown compliance with this regimen is challenging, as the treatmentduration is long and the application schedule is non-intuitive. Thecurrent study was designed to evaluate imiquimod cream in lowerconcentrations to permit a more intuitive daily-dosing regimen and ashortened treatment regimen (up to 8 weeks).

Efficacy

Efficacy was demonstrated for the primary efficacy measure as well asfor the secondary and tertiary efficacy measures for the 3.75% imiquimodcream and 2.5% imiquimod cream. Results for all efficacy measures forwhich statistical testing was performed were highly statisticallysignificant in both of the active treatment groups as compared withplacebo in both the ITT and PP populations.

Measures of wart reduction showed pronounced treatment effects for thehigher concentration product (complete clearance rates of 29.4%, 24.8%and 8.6%; ≥75% clearance rates of 38.7%, 31.2%, and 10.5%; mean percentchange in wart count of −40.9%, −37.7%, and −7.8%; and at least 50%reduction in wart count in 49.5%, 43.1%, and 20.0% of subjects in the3.75% imiquimod, 2.5% imiquimod, and placebo groups, respectively, inthe ITT population).

It should be noted that the primary efficacy variable used in this study(complete clearance of all warts, both Baseline and newly emerged, inall assessed anatomic areas) was very conservative. Warts were countedin all assessed anatomic areas without distinction as to those wartsidentified at baseline or those newly identified. In this study,subjects applied study medication to individual warts in variousanatomic areas identified at Baseline. Some subjects developed new wartsduring the study, and these new warts may have appeared in anatomicareas involved at Baseline as well as in newly involved anatomic areas.New warts were treated with study medication when they appeared, butreceived less than a full course of treatment, because treatment was notextended beyond 8 weeks from randomization/Day 1 visit. Subjects who didnot completely clear all warts by the Week 8/EOT visit were followed fora maximum 8 week no treatment period. As with evaluations during thedaily treatment phase, subjects were evaluated for the presence of EGWin all anatomic areas, and no distinction was made between baseline andnewly evident warts. As efficacy measures were based on completeclearance of all warts, not just warts presented at Baseline,development of new warts would potentially lower the complete andpartial clearance rates.

Subgroup analyses were performed for the primary efficacy variable. Ingeneral, the complete clearance rates increased in a dose-dependentmanner regardless of subgroup. The most striking subgroup effect wasobserved in the analysis by gender; the complete clearance rates wereconsistently higher in females than in males in all treatment groups.The higher absolute clearance rates in females than in males have beenseen previously with 5% imiquimod cream as well as with other topicaltreatments and may be due in part to the distribution of warts onfemales (eg, less keratinized skin).

In addition to gender subgroup, the complete clearance rates tended tobe higher in subjects with ≤7 warts at Baseline, in subjects with aBaseline wart area ≤70 mm², in subjects who took a rest period, insubjects with no previous imiquimod treatment, in subjects whose EGW wasfirst diagnosed within I year, and in subjects with baseline warts inthe anatomic areas with less keratinized skin such as the (perianalarea, the perineal area, on the glans penis, or on the vulva). Of note,baseline demographics for the population as a whole suggest that EGWs inthis study cohort were of relatively longstanding duration (mean/medianyears since diagnosis of 5.4/2.2 years).

Safety

Daily application of 3.75% or 2.5% imiquimod cream was generally welltolerated in this study. Few subjects discontinued the study due toadverse events. Very few serious adverse events were reported, and nonewere considered treatment related. The proportion of subjects withtreatment-related AEs was higher in the active treatment groups (19.5%and 18.4% in the 3.75% and 2.5% imiquimod, respectively) than withplacebo (2.9%), but there was no difference in the incidence ratesbetween imiquimod groups. Most AEs were mild or moderate in intensity,and resolved without sequelae.

The majority of AEs considered treatment-related occurred in the systemorgan class “General Disorders and Administrative Site Conditions”, andare not unanticipated with imiquimod. For the most part, theserepresented various application site reaction symptoms such as pain,irritation, and pruritus. The proportion of subjects with anyapplication site reaction was similar in the active treatment groups.

Anticipated reactions in the application area were also capturedseparately as local skin reactions (LSRs). The frequency and intensityof LSRs were higher in the active treatments compared with placebo.Erythema was the LSR reported with the greatest frequency and thegreatest mean intensity in all treatment groups. Severe intensity LSRswere similar between the active groups. Local skin reactions werecoincident with the treatment period and rapidly decreased whentreatment was concluded.

There was no evidence of clinically meaningful trends in vital signmeasurements or clinical laboratory measurements.

Conclusion

The 3.75% and 2.5% cream formulations of imiquimod demonstratedsubstantial efficacy for the treatment of EGW. All efficacy measures forwhich statistical testing was performed were significantly superior inthe 3.75% and 2.5% imiquimod treatment groups compared with placebo inboth the ITT and PP populations. The difference between 3.75% imiquimodand 2.5% imiquimod did not reach statistical significance at any timeduring the study. Treatment with either imiquimod formulation resultedin greater increases in local skin reactions compared with the placebocream: erythema was the LSR reported with the greatest frequency and thegreatest mean intensity in all treatment groups. For both active creams,the number and severity of local skin reactions decreased rapidly afterthe completion of treatment. The most frequently reported adverse eventswere application site reactions observed in the active treatment groups;however, few subjects discontinued the study as a result of adverseevents, indicating that these events were manageable and generally welltolerated.

Study Number: GW01-0801

Objectives: The primary objective of this study is to compare theefficacy and safety of 2.5% imiquimod cream and 3.75% imiquimod cream toplacebo cream, applied once daily for up to 8 weeks, in the treatment ofexternal genital warts (EGW). The secondary objective of this study isto provide information on recurrence of EGW.

Methodology:

This was a randomized, double-blind, placebo-controlled, multicenterstudy that compared the efficacy and safety of 2.5% imiquimod cream and3.75% imiquimod cream with that of placebo in the treatment of EGW.Subjects determined to be eligible during the screening period werestratified by gender and randomized in a 2:2:1 ratio to 2.5% imiquimodcream, 335% imiquimod cream, or placebo cream. Subjects were scheduledfor 1 prestudy screening visit, and then were scheduled for visits every2 weeks for up to 16 weeks during the evaluation period, depending uponclearance of all baseline and new warts. During the evaluation period,subjects applied investigative cream to the identified treatment areafor a maximum of 8 weeks. If the subject did not achieve complete wartclearance by the Week 8 visit (end of treatment, EOT), the subject wasmonitored for an additional maximum of 8 weeks. Subjects determined tohave achieved clearance of all warts at any time until Week 16 completedprocedures for the end-of-study (FOS) visit and were eligible toimmediately enter the follow-up period for determination of recurrence:During the follow-up period, subjects were monitored every 4 weeks forup to 12 weeks or until the recurrence of warts.

Clinical evaluations included counting of warts and assessment of localskin reactions (LSRs), and recording of adverse events (AEs) andconcomitant medications. At selected centers, photography was performedat designated visits. Laboratory tests were also performed prior totreatment and at the EOS visit to assess safety.

Number of Subjects (Total and for Each Treatment):

It was planned to enroll approximately 450 subjects in a 2:2:1 ratio.Actual enrollment was 470 subjects, and the ITT population and safetypopulation comprised 470 subjects (195 imiquimod 3.75%, 178 imiquimod2.5%, and 97 placebo). The per protocol (PP) population comprised 347subjects (137 imiquimod 3.75%, 134 imiquimod 2.5%, and 76 placebo).

Inclusion Criteria:

Subjects could participate in the study if they met the followinginclusion criteria:

-   -   1. Were willing and able to give informed consent—for subjects        under 18, the parent/legal guardian was required to give written        informed consent and the subject was required to provide written        assent in accordance with local regulations;

-   15. Were at least 12 years of age at the time of initial screening:

-   16. Were willing and able to participate in the study as    outpatients, making frequent visits to the study center during the    treatment and follow-up periods, and to comply with all study    requirements;

-   17. Had a diagnosis of external genital/perianal warts with at least    2 warts and no more than 30 warts located in one or more of the    following anatomic locations:    -   In both sexes: inguinal, perineal, and perianal areas;    -   In men: over the glans penis, penis shaft, scrotum, and        foreskin;    -   In women: on the vulva;

-   18. Had total wart areas of at least 10 mm²;

-   19. Were judged to be in good health based upon the results of a    medical history, physical examination, and safety laboratory    profile;

-   20. If female and of childbearing potential, had a negative serum    pregnancy test at Screening and a negative urine pregnancy test    prior to randomization and were willing to use effective    contraception; and

-   21. If male or a male partner of a female subject, were willing to    use condoms for sexual activities during the study.    Exclusion Criteria:

Subjects were excluded from the study if they met any of the followingcriteria:

-   -   1. Had received any topical and/or destructive treatments for        external genital warts within 4 weeks (within 12 months for        imiquimod and within 12 weeks for sinecatechins) prior to        enrollment (ie, the randomization visit);

-   22. Had received any of the following treatments within the    indicated time intervals prior to enrollment:

Washout Medication/Treatment Interval Any marketed or investigationalHPV vaccines 12 months Imiquimod 12 months Sinecatechins (Veregen ®) 12weeks  Interferon/Interferon inducer 4 weeks Cytotoxic drugs 4 weeksImmunomodulators or immunosuppressive therapies 4 weeks Oral antiviraldrugs (with the exception of oral 4 weeks acyclovir and acyclovirrelated drugs for suppressive or acute therapy herpes; or oseltamivirfor prophylaxis or acute therapy of influenza) Topical antiviral drugs(including topical acyclovir and 4 weeks acyclovir related drugs) in thewart areas Podophyllotoxin/Podofilox in the wart areas 4 weeks Oral andparenteral corticosteroids (inhaled/intranasal 4 weeks steroids arepermitted) Any topical prescription therapy for any conditions in 4weeks the wart areas Dermatologic/cosmetic procedures or surgeries inthe 4 weeks wart areas

-   23. Had any evidence (physical or laboratory) of clinically    significant or unstable disease and/or any condition that might have    interfered with the response to the study treatment or altered the    natural history of EGW;-   24. Were currently participating in another clinical study or had    completed another clinical study with an investigational drug or    device within the past 4 weeks;-   25. Had known or active chemical dependency or alcoholism as    assessed by the investigator;-   26. Had known allergies to study drug or any excipient n the study    cream;-   27. Were currently immunosuppressed or had a history of    immunosuppression;-   28. Had a planned surgery that would cause an interruption of study    treatment;-   29. Had sexual partners currently in treatment with an approved or    investigational treatment for EGW;-   30. Had any current or recurrent malignancies in the genital or    treatment area;-   31. Had any untreated or unstable genital infections (other than    genital warts);-   32. Had any of the following conditions:    -   known human immunodeficiency virus (HIV) infection;    -   current or past history of high risk HPV infection (eg, HPV 16,        18, etc);    -   an outbreak of herpes genitalis in the wart areas within 4 weeks        prior to enrollment;    -   internal (rectal, urethral, vaginal/cervical) warts that        required or were undergoing treatment;    -   a dermatological disease (eg, psoriasis) or skin condition in        the wart areas which may have caused difficulty with        examination;-   33. If female, had clinically significant abnormalities on pelvic    examination or had laboratory test results showing high-grade    pathology (eg, high-grade squamous intraepithelial lesion, moderate    or severe dysplasia, squamous cell carcinoma);-   34. If female, were nursing or pregnant or planned to become    pregnant during the study.    Test Product, Dose and Mode of Administration:

The test products were 2.5% imiquimod cream and 3.75% imiquimod cream.The reference therapy was placebo cream. Subjects applied the study drugin a thin layer once daily to each wart identified at Baseline and anynew wart that appeared during the treatment period.

A maximum of 1 packet (250 mg) of study drug was applied for a givendose (250 mg of 3.75% cream is equivalent to 9.375 mg imiquimod, and 250mg of 2.5% cream is equivalent to 6.25 mg imiquimod). Study drug wasapplied prior to normal sleeping hours and removed approximately 8 hourslater with mild soap and water. Subjects were to continue to apply studycream to all identified wart/wart areas until all warts were cleared.

The investigational products, 2.5% imiquimod cream and 3.75% imiquimodcream, contained imiquimod, isostearic acid, benzyl alcohol, cetylalcohol, stearyl alcohol, polysorbate 60, sorbitan monostearate, whitepetrolatum, glycerin, methyl paraben, propyl paraben, purified water,and xanthan gum. The placebo cream contained the same ingredients as theactive formulations with the exception of imiquimod.

Subjects meeting all inclusion and no exclusion criteria were randomlyassigned in a 2:2:1 ratio to 1 of the 3 treatment groups (2.5% imiquimodcream:3.7% imiquimod cream:or placebo cream).

Each dose of study drug was to be applied by the subject atapproximately the same time of day. To reduce the risk of study drugremoval from daily hygienic or physical activities, study drug was to beapplied just prior to the subject's normal sleeping hours.

Subjects were to wash the treatment area with mild soap and water beforeapplying the study medication, allow the area to dry thoroughly, andthen apply the study medication once daily. Subjects were to apply athin layer of study cream to each wart identified at Baseline and anynew wart that appeared during the treatment period. Only up to onepacket of study cream was to be applied per application.

The subjects were encouraged to leave study cream on for approximately 8hours, preferably during normal sleeping hours, and were not to wash thetreatment area, swim, shower or bathe, or have sexual contacts while thestudy medication was on the skin. Subjects could wash the study creamoff with soap and water any time after approximately 8 hours ofapplication. Subjects were to continue applying the study cream for amaximum of 8 weeks or until the investigator determined that they hadachieved complete clearance of all (baseline and new) warts. Subjectswere not to make up any missed doses.

Rest periods, or temporary interruptions of dosing due to intolerablelocal skin reactions, were allowed during the study if the investigatoror subject (or legal parent or guardian) decided that study drugapplication should be interrupted. Subjects who were placed on a restperiod were to be seen by the investigator prior to resuming treatmentwith study drug in order to assess if the recovery of the treatment sitewas sufficient. Doses missed due to a rest period were not counted asmissed doses in the assessment of subject compliance with the treatmentregimen. The study visit schedule and procedures were not to be altereddue to missed doses or rest periods. If a subject experienced a stronglocal reaction in one treatment area but not in other treated areas, thesubject could temporarily stop applying study cream in that affectedarea while continuing study treatment in the other areas.

During treatment period, any new warts appearing in any of theprotocol-defined anatomic locations were treated with the study cream.Neither the warts present at Baseline nor new warts were allowed to betreated during the no-treatment period (ie, from the Week 8/EOT visit tothe Week 16 visit).

Criteria for Evaluation:

Primary Efficacy Variables:

The primary efficacy variable was subject status with respect tocomplete clearance of all warts (baseline and new) in all anatomic areasat Week 16 (End of Study, EOS), as determined by the investigator.

Secondary and Tertiary Efficacy Variables

Secondary efficacy variables were the following:

-   -   Subject status with respect to partial clearance of baseline        warts, defined as at least 75% reduction in the number of        baseline warts at EOS/Week 16.    -   Percent change from Baseline to EOS in total number of warts.    -   Subject status with respect to complete clearance of all warts        at EOS, remaining cleared in all anatomic areas, as determined        by the investigator, through the end of the follow-up for        recurrence period, and    -   Time from Baseline to complete clearance of all warts, as        determined by the investigator.

Tertiary efficacy variables were the following:

-   -   Subject status with respect to complete clearance of all warts        (baseline and new) in all anatomic areas at EOT/Week 8, and    -   Subject status with respect to at least 50% reduction in the        number of baseline warts at EOS/Week 16.        Statistical Methods for Efficacy Analyses

Efficacy analyses were conducted on the ITT population and on the PPpopulation. For the primary efficacy variable, imputations were made formissing data points using last observation carried forward (LOCF,primary analysis), taking all missed observations as failure(sensitivity analysis), and using observed cases (supportive analysis).For the ITT population, subjects who had no post-baseline data wereincluded in the analysis carrying forward the baseline data. The PPpopulation analysis used observed cases except for complete clearanceand recurrence.

Analysis of the Primary Efficacy Variable

The primary efficacy endpoint, complete clearance rate at the EOS, wasanalyzed using Cochran-Mantel-Haenszel (CMH) statistics, stratifying bygender and site.

All pairwise comparisons of active treatment versus placebo were madeusing Hochberg's modified Bonferroni procedure. If either test wassignificant at a 0.025 level of significance, then that test wasconsidered significant. Otherwise, if both tests were significant at0.05, then both tests were considered significant. The 3.75% and 2.5%treatment groups were compared to each other at the 0.05 level ofsignificance if at least one of these treatment groups was found to bedifferent than the placebo using the Hochberg's test.

In the primary analysis of complete clearance rate, the Breslow-Daystatistic was tested at the 10% level for heterogeneity of the oddsratios across analysis sites. A finding of statistical significance inthis test was followed by exploratory analyses to characterize thesource of the heterogeneity.

Analysis of Secondary Efficacy Variables

The secondary efficacy variable partial clearance rate was analyzedusing Cochran-Mantel-Haenszel (CMH) statistics, stratifying by genderand site. The percent change from baseline to EOS in wart count wasanalyzed using analysis of covariance (ANCOVA), controlling for baselinewart count, gender, and analysis site. The proportion of subjects whowere clear prior to or at EOS and remained clear at the end of thefollow-up for recurrence period was summarized by frequency count and95% confidence interval. The time to complete clearance was analyzedusing the log rank test in the context of a Kaplan-Meier survivalanalysis.

For analysis of secondary efficacy variables, only the LOCF method wasused for the ITT population, and observed cases for the PP population.All data from interim visits were analyzed using visit windows.

The secondary efficacy variables were to be compared pairwise usingHochberg's modified Bonferroni procedure.

-   -   If at least one of the active arms was found to be superior to        placebo in the primary efficacy variable of complete clearance        according to Hochberg's modified Bonferroni procedure, the        secondary efficacy variable of partial (≥75%) clearance was        compared between each of the active arms and placebo.    -   If the secondary efficacy variable of partial (≥75%) clearance        was found to be superior to placebo in either of the active        treatment groups, then the secondary efficacy variable of        percent change from Baseline to EOS in wart count was tested.    -   If the secondary efficacy variable of percent change from        Baseline to EOS in wart count was found to be superior to        placebo in either of the active treatment groups, then the        secondary efficacy variable of complete clearance at EOS and        remained clear at the end of follow-up for recurrence period was        tested.    -   If the secondary efficacy variable of complete clearance at EOS        and remained clear at the end of follow-up for recurrence period        was found to be superior to placebo in either of the active        treatment groups, then the secondary efficacy variable of time        from Baseline to complete clearance was tested.

The percent change from Baseline in EGW count at each post-baselinevisit was summarized by mean, standard deviation, median, and range bytreatment group. The recurrence rate of warts was summarized bytreatment group and study visit using visit windows.

Analysis of Tertiary Efficacy Variables

The tertiary efficacy endpoints, complete clearance rate at EOT andsubject status with respect to at least a 50% reduction in baseline wartcount, were analyzed using Cochran-Mantel-Haenszel (CMH) statistics,stratifying on gender and site.

Visit Windows

For the analysis of wart counts, the data were summarized by analysisvisits. Analysis visits were assigned according to the actual study dayof the evaluation as illustrated in Table 98 below.

TABLE 98 Visit Windows Evaluation Period Target Analsis Visit Study DayDay Range Baseline 1 Study Day ≤ 1  Week 2 15  1 < Study Day ≤ 22 Week 429 22 < Study Day ≤ 36 Week 6 43 36 < Study Day ≤ 50 Week 8 57 50 <Study Day ≤ 64 End of Treatment (EOT) — Study Day ≤ 64 Week 10 71 64 <Study Day ≤ 78 Week 12 85 78 < Study Day ≤ 92 Week 14 99  92 < Study Day≤ 106 Week 16 113 106 < Study Day ≤ 127 End of Study EOS) —  Study Day ≤127 Target Follow-up Period Study Day Analysis Visit Post EOS Day RangeFollow-up Week 4 29  1 < Study Day ≤ 43 Follow-up Week 8 57 43 < StudyDay ≤ 71 Follow-up Week_12 85 71 < Study Day ≤ 99

All visits (scheduled or unscheduled) were mapped to an analysis visit.If more than 1 evaluation was assigned to an analysis visit, theevaluation with the lowest wart count within the window was used foranalysis. Study day was calculated as the date of evaluation minus thedate of randomization plus one except for the follow up visits. For thefollow up visits, study day was calculated as the date of evaluationminus the date of End of Study (EOS) visit plus one.

Safety Analyses

All safety variables Were analyzed using the safety population. Safetyvariables included the following:

-   -   Local skin reactions.    -   Rest periods during the treatment period:        -   The number and percentage by treatment group of subjects who            required a rest period (1 or more).        -   The number of dosing days missed due to rest periods.        -   The number of dosing days prior to the beginning of the            first rest period.    -   Adverse events.    -   Clinical laboratory test results.        Adverse Events

Adverse events were coded using Medical Dictionary for RegulatoryActivities (MedDRA, version 11.0) terminology. A treatment-emergent AEwas defined as an AE that began or worsened in severity after Day 1 andno more than 30 days after the last application of study drug. If an AEhad a completely missing start date, it was considered a “treatmentemergent” event, unless the stop date was prior to the date ofrandomization.

Treatment-emergent AEs and all AEs were summarized for each treatmentgroup by the overall incidence of at least one event, incidence bysystem organ class, and incidence by system organ class and preferredterm. Each subject contributed only once to each of the rates,regardless of the number of occurrences (events) the subjectexperienced.

Treatment-emergent AEs were summarized by severity (mild, moderate, orsevere) and by relationship to study product (related, not related).Events were considered not related to study product if the relationshipwas “not related” or “probably not related.” Similarly, related eventswere those that were “probably related” or “related.” An AE was assumedto be related to study drug if the relationship to study drug wasunknown. For AEs that occurred more than once, the AE that was mostrelated to study drug in that period was used in the summary of AEs byrelationship to study drug categories. Similarly, the AE with themaximum intensity in that period was used in the summary of AEs byseverity. If severity was missing or unknown, it was assumed to besevere.

The incidence of AEs was summarized for subgroup analysis by gender, byage subgroup, and by number of anatomic locations (ie, one locationversus multiple). Serious AEs (SAES) and AEs that led to discontinuationfrom the study were listed by subject.

Local Skin Reactions

The LSR intensities were summarized by frequency counts and mean scoreby treatment group and study visit for each LSR type. The LSRs weregraded as follows:

-   -   Erythema (0=None, 1=Faint to mild redness, 2=Moderate redness,        3=Intense redness),    -   Edema (0=None, 1=Mild visible or barely palpable        swelling/induration, 2=Easily palpable swelling/induration,        3=Gross swelling/induration),    -   Weeping/Exudate (0=None, 1=Minimal exudate, 2=Moderate exudate,        3=Heavy exudate),    -   Flaking/Scaling/Dryness (0=None, 1=Mild dryness/flaking,        2=Moderate dryness/flaking, 3=Severe dryness/flaking),    -   Scabbing/Crusting (0=None, 1=Crusting, 2=Serous scab, 3=Eschar),    -   Erosion/Ulceration (0=None, 2=Erosion, 3=Ulceration).

Erosion/ulceration intensity was originally collected as 0=None,1=Erosion, and 2=Ulceration. For consistency in the analysis of LSRintensities and sum score, these were recoded as 0=None, 2=Erosion, and3=Ulceration.

The most intense reaction (post-baseline) and incidence of any reaction(post-baseline) for each LSR type were also presented by frequencydistribution and mean score by treatment group. Data were analyzed usingwindows.

The LSR sum score (addition of 6 scores) was computed and summarized bytreatment group at each study visit.

Rest Periods

A rest period was a temporary interruption of dosing due to intolerableLSRs or other AEs. Doses missed due to a subject's noncompliance withthe treatment regimen were not considered a rest period. The start of arest period was the first date on which the study medication was notapplied for the reason of “rest period” on CRF page 20. The end of therest period was the first date of application following the start of therest period. The number and percentage of subjects who required a restperiod (I or more) were analyzed by treatment group using CMHstatistics. The number of dosing days missed due to rest periods and thenumber of dosing days prior to the beginning of the first rest periodwere analyzed using the Wilcoxon test. In this analysis, only subjectswho experienced a rest period were included.

Disposition of Subjects

The disposition of subjects for the evaluation period is shown in Table99 below:

TABLE 99 Subject Disposition-Evaluation Period (ITT Population) TotalImiquimod Cream Subjects, n (%) 3.75% 2.5% Placebo Overall Randomized195 178 97 470 Completed 136 (69.7)  121 (68.0)  66 (68.0) 323 (68.7) evaluation periods^(a) Not Cleared 82 (42.1) 87 (48.9) 56 (57.7) 225(47.9)  Cleared, Ended 4 (2.1) 3 (1.7) 4 (4.1) 11 (2.3)  Study Cleared,Entered 50 (25.6) 31 (17.4) 6 (6.2) 87 (18.5) Follow-up Discontinued 59(30.3) 57 (32.0) 31 (32.0) 147 (31.3)  evaluation period Reasons fordiscontinuation during evaluation period, n (%) Safety reasons 3 (1.5) 2(1.1) 1 (1.0) 6 (1.3) (AEs) Investigator's 1 (0.5) 0 0 1 (0.2) requestSubject's request 10 (5.1)  8 (4.5) 7 (7.2) 25 (5.3)  (not AE) Lack ofefficacy 0 1 (0.6) 0 1 (0.2) Noncompliance 1 (0.5) 4 (2.2) 0 5 (1.1) Useof concomitant 0 0 0 0 therapy Lost to follow-up 39 (20.0) 37 (20.8) 19(19.6) 95 (20.2) Other (not AE) 5 (2.6) 5 (2.8) 4 (4.1) 14 (3.0)  AE =adverse event. ^(a)Based on investigator assessment (CRF page 31),includes subjects who (1) cleared prior to or at EOS/Week 16, (2) notcleared at Week 16.

Of the 794 subjects who were screened, 470 (59.2%) were randomized and324 (40.8%) were screen failures. The most frequent reason for screenfailure (170 subjects [52.5%] out of 324 screen failures) was thatsubjects did not have a clinical diagnosis of EGW with at least 2 wartsand no more than 30 warts in one or more of the protocol-specifiedanatomic locations.

One hundred ninety five (195) subjects were randomized into the 3.75%imiquimod treatment group, 178 subjects were randomized into the 2.5%imiquimod treatment group, and 97 subjects were randomized into theplacebo group. Overall, 68.7% of subjects completed the study, and inthe individual treatment groups, 69.7%, 68.0%, and 68.0% in the 3.75%imiquimod, 2.5% imiquimod, and placebo groups, respectively, completedthe study. Lost to follow-up was the most common reason fordiscontinuation from the evaluation period, and accounted for withdrawalof approximately 20% of subjects in each treatment group. Among thetreatment groups, there was no appreciable difference in the percentagesof subjects who were lost to follow-up or the times at which they becamelost to follow-up. A sizeable number of subjects discontinued early, ie,had no post-Baseline visit: 15 of 59 (25.4%) in the 3.75% imiquimodgroup, 16 of 57 (28.1%) in the 2.5% imiquimod group, and 5 of 31 (16.1%)in the placebo group.

Follow-Up for Recurrence Period

Subject disposition for the follow-up period is shown in Table 100below:

TABLE 100 Subject Disposition-Follow-up Period (ITT Population)Imiquimod Cream Total Subjects, n (%) 3.75% 2.5% Placebo Overall Enteredfollow-up period 50 (100)  31 (100)  6 (100) 87 (100)  Completed study,no recurrence 41 (82.0) 20 (64.5) 6 (100) 67 (77.0) Subjects with EGWrecurrence  7 (14.0)  7 (22.6) 0 14 (16.1) Discontinued follow-upperiod^(a) 2 (4.0)  4 (12.9) 0 6 (6.9) Reasons for discontinuationduring follow-up, n (%) Subject's request (not AE) 0 1 (3.2) 0 1 (1.1)Lost to follow-up 2 (4.0) 3 (9.7) 0 5 (5.7) Other (not AE) 0 0 0 0 AE =adverse event. ^(a)Excludes subjects discontinued due to recurrence ofexternal genital warts.

Overall, 87 subjects entered the follow-up for recurrence period; 50from the 3.75% imiquimod treatment group, 31 from the 2.5% imiquimodtreatment group, and 6 from the placebo group. Only 6 subjects (2 and 4in the 3.75% and 2.5% imiquimod groups, respectively) discontinued thefollow-up for evaluation period. Of these, 5 subjects were lost tofollow-up and 1 subject was discontinued at his request.

Efficacy Evaluation

Datasets Analyzed

The number of subjects in each analysis population is presented in Table101 below.

TABLE 101 Number (%) of Subjects in Analysis Populations Imiquimod CreamPopulations 3.75% 2.5% Placebo Overall ITT population 195 178 97 470 PPpopulation 137 134 76 347 Safety population 195 178 97 470 Follow-up forRecurrence 50 31 6 87 population

A total of 470 subjects were included in the ITT and safety populations.Of these, 347 subjects were included in the PP population. A total of 87subjects elected to enter the follow-up period and comprised thefollow-up for recurrence population.

Demographic and Other Baseline Characteristics

Prestudy/Baseline Demographics

Demographic and baseline characteristics for the ITT population areshown in Table 102 below.

TABLE 102 Demographic Summary by Treatment Group-ITT PopulationImiquimod Cream 3.75% 2.5% Placebo Overall (N = 195) (N = 178) (N = 97)(N = 470) Age in years Mean (SD) 32.5 (11.6) 32.7 (11.3) 30.5 (10.6)32.2 (11.3) Median 29.0 30.0 27.0 29.0 Minimum, 18.0, 81.0 17.0, 78.018.0, 75.0 17.0, 81.0 Maximum Sex, n (%) Male   95 (48.7)   83 (46.6)  47 (48.5)  225 (47.9) Female  100 (51.3)   95 (53.4)   50 (51.5)  245(52.1) Race, n (%)         White  147 (75.4)  122 (68.5)   66 (68.0) 335 (71.3) Black/African   41 (21.0)   47 (26.4)   28 (28.9)  116(24.7) American Other   7 (3.6)   9 (5.1)   3 (3.1)   19 (4.0)Ethnicity, n (%)         Hispanic   31 (15.9)   25 (14.0)   11 (11.3)  67 (14.3) Non-Hispanic  164 (84.1)  153 (86.0)   86 (88.7)  403 (85.7)SD = standard deviation.

Demographic characteristics were similar among the 3 treatment groups.Slightly more than half of the subjects were female. Overall, 71.3% ofsubjects were White, and more than 84% of subjects in every treatmentgroup were non-Hispanic. The mean age ranged from 30.5 years in theplacebo group to 32.7 years in the 2.5% imiquimod treatment group.

Medical History

The most frequently-reported concomitant medical conditions werehypertension/high blood pressure (42 subjects), seasonal allergies (27subjects), and depression (21 subjects).

External Genital Warts Treatment History

Previous EGW treatment was reported by 493%, 42.7%, and 33.0% ofsubjects in the 3.75% imiquimod, 2.5% imiquimod, and placebo groups,respectively. Cryotherapy was the most frequently reported treatment,and had been performed in 28.2% of the subjects in the 3.75% imiquimodtreatment group, 18.5% of subjects in the 2.5% imiquimod treatmentgroup, and 13.4% of subjects in the placebo group. Other treatmentsincluded acetic acid (in a total of 42 subjects), imiquimod (in 33subjects), podophyllotoxin (in 23 subjects), laser therapy (in 22subjects), “other” treatments (in 20 subjects), surgical excision (in 12subjects), podophyllin (in 9 subjects), and electrodessication (in 3subjects).

Prior and Concomitant Medications

Sixteen subjects (8.2%) in the 3.75% imiquimod treatment group, 12subjects (6.7%) in the 2.5% imiquimod treatment group, and 4 subjects(4.1%) in the placebo group were taking prior medications, ie,medications that were discontinued prior to the date of randomization.The most common prior medications were antibacterials for systemic usein 3.6% of the 3.75% imiquimod treatment group, 3.9% of the 2.5%imiquimod treatment group, and 2.1% of the placebo group.

Ninety-two subjects (47.2%) in the 3.75% imiquimod treatment group, 94subjects (52.8%) in the 2.5% imiquimod treatment group, and 45 subjects(46.4%) in the placebo received one or more concomitant medicationsduring the study. The following classes of concomitant medications werereceived by more than 10% of the subjects in one or more treatmentgroups:

-   -   Analgesics, received by 18.5% of the 3.75% imiquimod treatment        group, 13.5% of the 2.5% imiquimod treatment group, and 20.6% of        the placebo group;    -   Anti-inflammatory and anti-rheumatic products, received by 10.3%        of the 3.75% imiquimod treatment group, 13.5% of the 2.5%        imiquimod treatment group, and 12.4% of the placebo group;    -   Sex hormones and modulators of the genital system, by 7.7% of        the 3.75%® imiquimod treatment group, 10.1% of the 2.5%        imiquimod treatment group, and 9.3% of the placebo group.        Baseline Number of External Genital Warts

A summary of the external genital wart counts at Baseline and otherbaseline data relevant to subjects' EGW are presented in Table 103below:

TABLE 103 Baseline External Genital Warts Data by Treatment Group-ITTPopulation Imiquimod Cream 3.75% 2.5% Placebo Overall (N = 195) (N =178) (N = 97) (N = 470) Total wart area (mm²) Mean (SD) 150.9 (458.7)160.2 (334.8) 140.7 (248.6) 152.3 (377.0) Median  52 68 73  61 Minimum,Maximum 10, 5579 10, 3212 6, 1969 6, 5579 Total wart count Mean (SD) 8.6 (6.4)  9.2 (6.7)  11.6 (8.8)  9.4 (7.1) Median  7  7  8  7 Minimum,Maximum 2, 30 2, 30 2, 30 2, 30 Years Since Diagnosis Mean  4.2  4.8 3.6  4.3 Standard Deviation  6.6  7.8  6.1  7.0 Median  1.4  1.5  1.3 1.4 Minimum, Maximum 0.0, 33.3 0.0, 53.7 0.0, 33,7 0.0, 53.7 Anatomiclocation, Males^(a), n  95 83 47 225 Inguinal  29 (30.5) 20 (24.1) 13(27.7)  62 (27.6) Perineal   7 (7.4)  6 (7.2)  4 (8.5)  17 (7.6)Perianal   6 (6.3)  8 (9.6)  2 (4.3)  16 (7.1) Glans penis   9 (9.5)  6(7.2)  5 (10.6)  20 (8.9) Penis shaft  77 (81.1) 71 (85.5) 42 (89.4) 190(84.4) Scrotum  27 (28.4) 29 (34.9)  8 (17.0)  64 (28.4) Foreskin   3(3.2)  4 (4.8)  1 (2.1)   8 (3.6) Anatomic location, Females^(b), n 10095 50 245 Inguinal  17 (17.0) 11 (11.6)  6 (12.0)  34 (13.9) Perineal 48 (48.0) 43 (45.3) 22 (44.0) 113 (46.1) Perianal  44 (44.0) 52 (54.7)22 (44.0) 118 (48.2) Vulva  59 (59.0) 60 (63.2) 32 (64.0) 151 (61.6)Number of treatment anatomic areas, n (%)-Males^(a) Total Males  95(100) 83 (100) 47 (100) 225 (100) 1  47 (49.5) 38 (45.8) 25 (53.2) 110(48.9) 2  34 (35.8) 31 (37.3) 16 (34.0)  81 (36.0) 3  13 (13.7) 12(14.5)  6 (12.8)  31 (13.8) 4   1 (1.1)  2 (2.4) 0  3 (1.3) Number oftreatment anatomic areas, n (%)-Females^(b) Total Females   100 (100)  95 (100)   50 (100)  245 (100) 1   49 (49.0)   40 (42.1)   26 (52.0) 115 (46.9) 2   36 (36.0)   40 (42.1)   17 (34.0)  93 (38.0) 3   13(13.0)   14 (14.7)    6 (12.0)  33 (13.5) 4    2 (2.0)    1 (1.1)    1(2.0)   4 (1.6) SD = standard deviation. ^(a)Denominator based on thenumber of males in treatment group. ^(b)Denominator based on the numberof females in treatment group.

The mean total wart area was 152.3 mm² overall, and ranged from 140.7mm² in the placebo group to 160.2 mm² in the 2.5% imiquimod treatmentgroup. The mean total wart count was 9.4 warts overall, and ranged from8.6 warts in the 3.75% imiquimod treatment group to 11.6 warts in theplacebo group. In males, the most commonly affected anatomic areas werethe penis shaft (84.4%), the scrotum (28.4%), and the inguinal area(27.6%). In females, the most commonly affected anatomic areas were thevulva (61.6%), the perianal area (48.2%), and the perineal area (46.1%).The anatomic distribution of warts was fairly consistent across thetreatment groups. More than 50% of subjects in both gender subgroups hadtwo or more anatomic locations affected with warts at Baseline.

Measurements of Treatment Compliance

Treatment compliance data was collected and analyzed. Compliance wasbased on the number of applications received (where a rest period daywas counted as an application) divided by the number of intendedapplications, or by the number of packets used (where a rest period daywas counted as a packet used) divided by the number of packets intendedto be used per the protocol-defined treatment regimen, whichever wasgreater. Noncompliance with the treatment regimen was defined ascompliance less than 75% or greater than 125%.

The overall mean treatment compliance was 84.3% in the 3.75% imiquimodgroup, 84.7% in the 2.5% imiquimod group, and 86.8% in the placebogroup. Of the 123 subjects excluded from the PP population in thisstudy, 122 exclusions were the result of noncompliance with thetreatment regimen, including many subjects who were lost to follow-up.Compliance rates were slightly higher in subjects who cleared their EGWduring the study (90.9%, 88.5%, and 87.2% in the 3.75% imiquimod, 2.5%imiquimod, and placebo groups, respectively) compared with, subjects whodid not clear (81.5%, 83.8%, and 86.8% in the 3.75% imiquimod, 2.5%imiquimod, and placebo groups, respectively).

Efficacy Results

Complete Clearance of all Warts

Complete Clearance Rates at End of Study

The primary efficacy variable in this study was the proportion ofsubjects with complete clearance of all warts (those present at Baselineand new warts) at EOS (ie, 8 weeks after EOT). The primary analysis wasperformed on the ITT population with imputation (LOCF) for missing datapoints. The results of the analyses on the population, overall and bygender, are shown in Table 104 below. Results are presented graphicallyfor the ITT population in FIG. 25.

TABLE 104 Proportion of Subjects with Complete Clearance of Warts at theWeek 16/End of Study (EOS) Visit Imiquimod Cream 3.75% 2.5% Placebo ITTPopulation (LOCF) n/N^(a) (%) 53/195 (27.2) 34/178 (19.1) 10/97 (10.3)95% CI 21.1, 34.0 13.6, 25.7 5.1, 18.1 P value vs placebo <0.001** 0.065— P value vs 2.5%   0.061 — — Imiquimod Cream Males n/N^(a) (%) 19/95(20.0) 11/83 (13.3)  2/47 (4.3) 95% confidence interval 12.5, 29.5 6.8,22.5 0.5, 14.5 P value vs Placebo   0.015** 0.110 — P value vs 2.5%  0.236 — — Imiquimod Cream Females n/N^(a) (%) 34/100 (34.0) 23/95(24.2)  8/50 (16.0) 95% confidence interval 24.8, 44.2 16.0, 34.1 7.2,29.1 P value vs Placebo   0.017** 0.255 — P value vs 2.5%   0.147 — —Imiquimod Cream LOCF = last observation carried forward, 95% CI = 95%confidence interval. ^(a)n/N = number of subjects with completeclearance at end of study divided by the number of subjects analyzed. Pvalues are from Cochran-Mantel-Haenszel test, stratified by gender andanalysis site (overall population) or stratified by analysis site(gender subgroups), taking 2 treatment groups at a time. The P valuesmarked with ** are statistically significant using Hochberg's modifiedBonferroni procedure. Confidence intervals are calculated using exactbinomial statistics. Breslow-Day P values for ITT Population (LOCF),males, are 3.75% Imiquimod Cream vs Placebo = 0.357, 2.5% ImiquimodCream vs Placebo = 0.245, and 3.75% Imiquimod Cream vs 2.5% ImiquimodCream = 0.708. Breslow-Day P values for ITT Population (LOCF), females,are 3.75% Imiquimod Cream vs Placebo = 0.358, 2.5% Imiquimod Cream vsPlacebo = 0.310, and 3.75% Imiquimod Cream vs 2.5% Imiquimod Cream =0.178.

In the ITT population, the rate of complete clearance of EGW at EOS wassignificantly higher (P<0.001) in the 3.75% imiquimod group (27.2%)compared with placebo (10.3%); the difference in rate of completeclearance between the 2.5% imiquimod group (19.1%) and the placebo group(10.3%) did not attain statistical significance (P=0.065). The 3.75%imiquimod group had a higher rate of complete clearance than the 2.5%imiquimod group, but the difference between the 2 active treatmentgroups was not statistically significant (P=0.061).

Results were similar in the by-gender analyses. Complete clearance ratesat EOS were statistically significantly higher with 3.75% imiquimod thanwith placebo in both genders. There was no significant difference incomplete clearance rates at EOS between 2.5% imiquimod and placebo ineither gender. In all treatment groups, the complete clearance rateswere consistently higher in females than in males.

Rates of complete clearance at EOS in the ITT population are illustratedin FIG. 25.

The primary efficacy variable was analyzed for the PP population,overall and by gender, using observed cases (OC). Results for the PPpopulation are shown in Table 105 below.

TABLE 105 Proportion of Subjects with Complete Clearance of Warts at theWeek 16/ End of Study (EOS) Visit-PP Population (Observed Cases)Imiquimod Cream 3.75% 2.5% Placebo PP Population (OC), at EOS N   137134 76 n/N^(a) (%) 46/137 (33.6) 32/134 (23.9) 9/76 (11.8) 95% CI 25.7,42.1 16.9, 32.0 5.6, 21.3 P value vs placebo  <0.001**  0.044** — Pvalue vs 2.5% Imiquimod Cream    0.060 — — Males n/N^(a) (%) 17/69(24.6) 10/63 (15.9) 2/34 (5.9) 95% confidence interval 15.1, 36.5 7.9,27.3 0.7, 19.7 P value vs Placebo    0.023**  0.161 — P value vs 2.5%Imiquimod Cream    0.286 — — Females n/N^(a) (%) 29/68 (42.6) 22/71(31.0) 7/42 (16.7) 95% confidence interval 30.7, 55.2 20.5, 43.1 7.0,31.4 P value vs Placebo    0.005**  0.140 — P value vs 2.5% ImiquimodCream    0.121 — — 95% CI = 95% confidence interval, OC = observedcases. ^(a)n/N = number of subjects with complete clearance at end ofstudy divided by the number of subjects analyzed. P values are fromCochran-Mantel-Haenszel test, stratified by gender and analysis site(overall population) or stratified by analysis site (gender subgroups),taking 2 treatment groups at a time. P values marked with ** arestatistically significant using Hochberg's modified Bonferroniprocedure. Confidence intervals were calculated using the exact binomialdistribution. Complete clearance was carried forward once achieved.

In the PP population, the complete clearance rates at EOS were higherthan those in the ITT population for all treatment groups: 33.6% in the3.75% imiquimod group, 23.9% in the 2.5% imiquimod group, and 11.8% inthe placebo group. The larger responses in the active treatment groupswere statistically significant compared with placebo (P<0.001 for 3.75%imiquimod vs placebo; P=0.044 for 2.5% imiquimod vs placebo). As was thecase in the ITT population, the complete clearance rate was larger inthe 3.75% imiquimod group than in the 2.5% imiquimod group, but thedifference between the 2 active treatment groups was not statisticallysignificant.

Results were similar in the by-gender analyses. Complete clearance ratesat EOS were statistically significantly higher with 3.75% imiquimod thanwith placebo in both genders. There was no significant difference incomplete clearance rates at EOS between 2.5% imiquimod and placebo ineither gender. In all treatment groups, the complete clearance rateswere consistently higher in females than in males.

Rates of complete clearance at EOS in the PP population are illustratedin FIG. 26.

Complete Clearance Rates at End of Treatment

A summary of the complete clearance at EOT for the ITT population,overall and by gender, is provided in Table 106.

TABLE 106 Proportion of Subjects with Complete Clearance of Warts at Endof Treatment-ITT Population (LOCF) Imiquimod Cream 3.75% 2.5% PlaceboITT Population (LOCF) n/N^(a) (%) 43/195 (22.1) 20/178 (11.2) 5/97 (5.2)95% CI 16.4, 28.5 7.0, 16.8 1.7, 11.6 P value vs placebo <0.001** 0.090— P value vs 2.5% imiquimod cream   0.004** — — Males n/N^(a) (%) 14/95(14.7)  6/83 (7.2) 1/47 (2.1) 95% CI 8.3, 23.5 2.7, 15.1 0.1, 11.3 Pvalue vs placebo   0.027 0.227 — P value vs 2.5% imiquimod cream   0.123— — Females n/N^(a) (%) 29/100 (29.0) 14/95 (14.7) 4/50 (8.0) 95% CI20.4, 38.9 8.3, 23.5 2.2, 19.2 P value vs placebo   0.003** 0.215 — Pvalue vs 2.5% imiquimod cream   0.017** — — LOCF = last observationcarried forward, 95% CI = 95% confidence interval. ^(a)n/N = number ofsubjects with complete clearance at end of treatment divided by thenumber of subjects analyzed. P values are from Cochran-Mantel-Haenszeltest, stratified by gender and analysis site (overall population) orstratified by analysis site (gender subgroups), taking 2 treatmentgroups at a time. P values marked with ** are statistically significantusing Hochberg's modified Bonferroni procedure. Confidence intervalswere calculated using the exact binomial distribution.

At Week 8/EOT, 22.1% of subjects in the 3.75% imiquimod group, 11.2% ofsubjects in the 2.5% imiquimod group, and 5.2% of subjects in theplacebo group had attained complete clearance. The overall completeclearance rate at EOT was significantly higher in the 3.75% imiquimodgroup compared with placebo (P<0.001) and compared with 2.5% imiquimod(P=0.004). The difference between 2.5% imiquimod and placebo was notstatistically significant.

The complete clearance rate at EOT was significantly higher in the 3.75%imiquimod group compared with placebo and compared with 2.5% imiquimodonly in the female subgroup. The difference between 2.5% imiquimod andplacebo was not statistically significant in either gender subgroup. Inall treatment groups, the complete clearance rates were consistentlyhigher in females than in males.

A summary of the complete clearance at Ear for the PP population,overall and by gender, is provided in Table 107.

TABLE 107 Proportion of Subjects with Complete Clearance of Warts at Endof Treatment-PP Population (Observed Cases) Imiquimod Cream 3.75% 23%Placebo PP Population (OC) at EOT n/N^(a) (%) 36/137 (26.3) 19/134(14.2) 4/76 (5.3) 95% CI 19.1, 34.5 8.8, 21.3 1.5, 12.9 P value vsplacebo <0.001** 0.038** — P value vs 2.5% imiquimod cream   0.015** — —Males n/N^(a) (%) 12/69 (17.4)  6/63 (9.5) 1/34 (2.9) 95% CI 9.3, 28.43.6, 19.6 0.1, 15.3 P value vs placebo   0.069 0.267 — P value vs 2.5%imiquimod cream   0.290 — — Females n/N^(a) 24/68 (35.3) 13/71 (18.3)3/42 (7.1) 95% CI 24.1,47.8 10.1,29.3 1.5, 19.5 P value vs placebo<0.001** 0.079 — P value vs 2.5% imiquimod cream   0.025** — — 95% CI =95% confidence interval, OC = observed cases. ^(a)n/N = number ofsubjects with complete clearance at end of treatment divided by thenumber of subjects analyzed. P values are from Cochran-Mantel-Haenszeltest, stratified by gender and analysis site (overall population) orstratified by analysis site (gender subgroups), taking 2 treatmentgroups at a time. P values marked with ** are statistically significantusing Hochberg's modified Bonferroni procedure. Confidence intervalswere calculated using the exact binomial distribution. Completeclearance was carried forward once achieved.

In the PP population, the EOT complete clearance rate was significantlyhigher in both active treatment groups compared with placebo (P<0.001for 3.75% imiquimod vs placebo; and P=0.038 for 2.5% imiquimod vsplacebo), The complete clearance rate at EOT was significantly greaterwith 3.75% imiquimod than with 2.5% imiquimod (P=0.015).

In the female subgroup, the complete clearance rate at EOT wassignificantly higher in the 3.75% imiquimod group compared with placeboand compared with 2.5% imiquimod. In the male subgroup, there was nosignificant difference between any of the treatment groups. In alltreatment groups, the complete clearance rates were consistently higherin females than in males.

Complete Clearance Rates by Visit Week

A by-visit summary of complete clearance rates in the ITT populationduring the evaluation period is shown graphically in FIG. 27.

As shown in FIG. 27, the complete clearance rate was significantlyhigher in the 3.75% imiquimod group compared with placebo at allassessment time points after Week 2; this includes the Week 8/end oftreatment assessment and the Week 16/end of study assessment. Thecomplete clearance rate was significantly higher in the 2.5% imiquimodgroup compared with placebo at Weeks 6, 10, 12, and 14. The clearancerate was higher in the 3.75% imiquimod group than in the 2.5% imiquimodgroup and the difference was statistically significant at Week 8 (end oftreatment), and at Weeks 10, 12, and 14.

In female subjects, the complete clearance rate was significantly higherin the 3.75% imiquimod group compared with placebo at all assessmenttime points after Week 2, and was significantly higher compared with2.5% imiquimod at Weeks 4, 6, 8, 12, and 14. In male subjects, thecomplete clearance rate was significantly higher in the 3.75% imiquimodgroup compared with placebo at Weeks 10, 12, 14, and 16. There was nostatistically significant difference in complete clearance rate between2.5% imiquimod and placebo in either gender.

A by-visit summary of complete clearance rates in the PP populationduring the evaluation period is shown in FIG. 28.

Results in the PP population were similar to those in the ITTpopulation. The complete clearance rate was significantly higher in the3.75% imiquimod and 2.5% imiquimod groups compared with placebo at allassessment time points after Week 2. The clearance rate was higher inthe 3.75% imiquimod group than in the 2.5% imiquimod group and thedifference was statistically significant at Weeks 8, 12, and 14.

In female subjects, the complete clearance rate was significantly higherin the 3.75% imiquimod group compared with placebo at all assessmenttime points after Week 2, and was significantly higher compared with2.5% imiquimod at Weeks 8 and 12. In male subjects, the completeclearance rate was significantly higher in the 3.75% imiquimod groupcompared with placebo at, Weeks 10, 12, 14, and 16. The only significantdifference in complete clearance rate between 2.5% imiquimod and placebooccurred in females at Week 10.

Partial Clearance Rates

Partial (≥75%) Clearance Rates at End of Study

The proportion of subjects, overall and by gender, who had a partialclearance (≥75% reduction from Baseline in wart count) during the studyis summarized in Table 108 and FIG. 29 for the ITT population. Partialclearance was defined as at least a 75% reduction in the number of wartsin the treatment area compared with Baseline.

TABLE 108 Proportion of Subjects with Partial (≥75%) Clearance at End ofStudy- ITT Population IMIQUIMOD CREAM 3.75% 2.5% PLACEBO ITT Population(LOCF) at EOS n/N^(a) (%) 74/195 (37.9) 48/178 (27.0) 13/97 (13.4) 95%CI 31.1, 45.2 20.6, 34.1 7.3, 21.8 P value vs Placebo <0.001** 0.010** —P value vs 2.5% Imiquimod   0.023** — — Cream Males n/N^(a) (%) 29/95(30.5) 15/83 (18.1)  3/47 (6.4) 95% CI 21.5, 40.8 10.5, 28.0 1.3, 17.5 Pvalue vs Placebo   0.001** 0.060 — P value vs 2.5% Imiquimod   0.067 — —Cream Females n/N^(a) (%) 45/100 (45.0) 33/95 (34.7) 10/50 (20.0) 95% CI35.0, 55.3 25.3, 45.2 10.0, 33.7 P value vs Placebo   0.002** 0.071 — Pvalue vs 2.5% Imiquimod   0.150 — — Cream 95% CI = 95% confidenceinterval. ^(a)n/N = number of subjects with complete clearance at end ofstudy divided by the number of subjects analyzed Partial clearance wasdefined as at least a 75% reduction in the number of warts in thetreatment area compared with Baseline. P values are fromCochran-Mantel-Haenszel test, stratified by gender and analysis site(overall population) or stratified by analysis site (gender subgroups),taking 2 treatment groups at a time. The P values marked with ** arestatistically significant using Hochberg's modified Bonferroniprocedure. Confidence intervals were calculated using the exact binomialdistribution

In the ITT population, the difference in the partial (≥75%©) clearancerate at EOS between each of the imiquimod treatment groups and placebowas statistically significant. The partial (≥75%) clearance rate in the3.75% imiquimod group was significantly higher than that in the 2.5%imiquimod treatment group.

In the by-gender analyses, the ≥75% clearance rate at EOS wassignificantly higher in the 3.75% imiquimod group compared with placebofor both males and females. There was no significant difference between2.5% imiquimod and placebo, or between the 3.75% and 2.5% imiquimodgroups. In all treatment groups, the ≥75% clearance rates wereconsistently higher in females than in males.

A summary of the partial (≥75%) clearance rate at EOS for the PPpopulation, overall and by gender, is presented in Table 109. The ≥75%clearance rates at EOS are presented graphically in FIG. 30.

TABLE 109 Proportion of Subjects with Partial (≥75%) Clearance at End ofStudy-PP Population (Observed Cases) IMIQUIMOD CREAM 3.75% 2.5% PLACEBOPP Population (OC), at EOS n/N^(a) (%) 64/137 (46.7) 46/134 (34.3) 10/76(13.2) 95% CI 38.1, 55.4 26.3, 43.0 6.5, 22.9 P value vs Placebo<0.001** <0.001** — P value vs 2.5% Imiquimod   0.048** — — Cream Malesn/N^(a) (%) 27/69 (39.1) 14/63 (22.2)  2/34 (5.9) 95% CI 27.6, 51.612.7, 34.5 0.7, 19.7 P value vs Placebo <0.001**   0.041** — P value vs2.5% Imiquimod   0.090 — — Cream Females n/N^(a) (%) 37/68 (54.4) 32/71(45,1)  8/42 (19.0) 95% CI 41.9, 66.5 33.2, 57.3 8.6, 34.1 P value vsPlacebo <0.001**   0.009** — P value vs 2.5% Imiquimod   0.257 — — Cream95% CI = 95% confidence interval. ^(a)n/N = number of subjects withcomplete clearance at end of study divided by the number of subjectsanalyzed Partial clearance was defined as at least a 75% reduction inthe number of warts in the treatment area compared with Baseline. Pvalues are from Cochran-Mantel-Haenszel test, stratified by gender andanalysis site (overall population) or stratified by analysis site(gender subgroups), taking 2 treatment groups at a time. The P valuesmarked with ** are statistically significant using Hochberg's modifiedBonferroni procedure. Confidence intervals were calculated using theexact binomial statistics.

In the PP population, the partial (≥75%) clearance rate at EOS washigher in the active treatment groups than in the placebo group. Thedifference between each of the imiquimod treatment groups and placebowas statistically significant (P<0.001). The partial (≥75%) clearancerate in the 3.75% imiquimod group was significantly higher (P=0.048)than that in the 2.5% imiquimod treatment group. The partial (≥75%)clearance rates were statistically significantly higher in the 3.75%imiquimod group compared with placebo at all analysis time points afterWeek 0.

As in the overall PP population, the ≥75% clearance rate wassignificantly higher with 3.75% imiquimod and with 2.5% imiquimod versusplacebo in either gender. There was no statistically significantdifference between the active treatment groups in either gender.

Partial (≥75%) Clearance Rates at End of Treatment

The proportion of subjects who had a 75% or greater reduction fromBaseline in wart count at EOT is shown in Table 110.

TABLE 110 Proportion of Subjects with Partial (≥75%) Clearance at End ofTreatment-ITT Population (LOCF) IMIQUIMOD CREAM 3.75% 2.5% PLACEBO ITTPopulation (LOCF) at EOT N 195 178 97 n/N^(a) (%) 62/195 (31.8) 40/178(22.5) 9/97 (9.3) 95% CI 25.3, 38.8 16.6, 29.3 4.3, 16.9 P value vsPlacebo <0.001**   0.008** — P value vs 2.5% Imiquimod   0.037** — —Cream Males n/N^(a) (%) 24/95 (25.3) 14/83 (16.9) 3/47 (6.4) 95% CI16.9, 35.2 9.5, 26.7 1.3, 17.5 P value vs Placebo   0.007**   0.093 — Pvalue vs 2.5% Imiquimod   0.174 — — Cream Females n/N^(a) (%) 38/100(38.0) 26/95 (27.4) 6/50 (12.0) 95% CI 28.5, 48.3 18.7, 37.5 4.5, 24.3 Pvalue vs Placebo   0.001**   0.040** — P value vs 2.5% Imiquimod   0.114— — Cream LOCF = last observation carried forward, 95% CI = 95%confidence interval. ^(a)n/N = number of subjects with completeclearance at end of study divided by the number of subjects analyzedPartial clearance was defined as at least a 75% reduction in the numberof warts in the treatment area compared with Baseline. P values are fromCochran-Mantel-Haenszel test, stratified by gender and analysis site(overall population) or stratified by analysis site (gender subgroups),taking 2 treatment groups at a time. The P values marked with ** arestatistically significant using Hochberg's modified Bonferroniprocedure. Confidence intervals were calculated using the exact binomialstatistics.

In the overall ITT population, the ≥75% clearance rate at EOT wassignificantly higher in the active treatment groups than in the placebogroup, and was significantly higher with 3.75% than with 2.5% imiquimod.

The ≥75% clearance rate at EOT was significantly higher with 3.75%imiquimod compared with placebo in either gender, and for 2.5% imiquimodversus placebo in the female subgroup. There was no significantdifference between 3.75% and 2.5% imiquimod in either gender.

The ≥75% clearance rate at EOT for the PP population is provided inTable 111.

TABLE 111 Proportion of Subjects with Partial (≥75%) Clearance at End ofTreatment-PP Population (Observed Cases) IMIQUIMOD CREAM 3.75% 2.5%PLACEBO PP Population (OC), at EOT n/N^(a) (%) 54/137 (39.4) 39/134(29.1) 6/76 (7.9) 95% CI 31.2, 48.1 21.6, 37.6 3.0, 16.4 P value vsPlacebo <0.001** <0.001** — P value vs 2.5% Imiquimod   0.062 — — CreamMales n/N^(a) (%) 21/69 (30.4) 14/63 (22.2) 2/34 (5.9) 95% CI 19.9, 42.712.7, 34.5 0.7, 19.7 P value vs Placebo   0.010**   0.050** — P value vs2.5% Imiquimod   0.429 — — Cream Females n/N^(a) (%) 33/68 (48.5) 25/71(35.2) 4/42 (9.5) 95% CI 36.2, 61.0 242, 47.5 2.7, 22.6 P value vsPlacebo <0.001**   0.006** — P value vs 2.5% Imiquimod   0.077 — — Cream95% CI = 95% confidence interval, OC = observed cases, EOT = end oftreatment ^(a)n/N = number of subjects with complete clearance at end ofstudy divided by the number of subjects analyzed Partial clearance wasdefined as at least a 75% reduction in the number of warts in thetreatment area compared with Baseline. P values are fromCochran-Mantel-Haenszel test, stratified by gender and analysis site(overall population) or stratified by analysis site (gender subgroups),taking 2 treatment groups at a time. The P values marked with ** arestatistically significant using Hochberg's modified Bonferroniprocedure. Confidence intervals were calculated using the exact binomialstatistics.

In the overall PP population, the ≥75% clearance rate at EOT wassignificantly higher in the active treatment groups than in the placebogroup. There was no significant difference between the active treatmentgroups.

The ≥75% clearance rate at EOT was significantly higher with both activetreatments compared with placebo in both genders. There was nosignificant difference between the 3.75% and 2.5% imiquimod groups ineither gender.

Partial (≥75%) Clearance Rails by Analysis Visit

Over the course of the study, the partial (≥75%) clearance rates werestatistically significantly higher in the 3.75% imiquimod group comparedwith placebo at all analysis time points after Week 2, and weresignificantly higher for 3.75% compared with 2.5% imiquimod at allanalysis time points after Week 4. The partial (≥75%) clearance rateswere significantly higher for 2.5% imiquimod vs placebo at Weeks 4, 6,8, 10, 14, and 16.

In both genders, the difference between each of the imiquimod treatmentgroups and placebo was statistically significant at Week 16. The partial(≥75%) clearance rates were statistically significantly higher in the3.75% imiquimod group compared with placebo at Week 6 and thereafter inmales, and at Week 4 and thereafter in females.

The partial (≥75%) clearance rates were statistically significantlyhigher in the 3.75% imiquimod group compared with placebo at allanalysis time points after Week 0.

Subjects with at Least a 50% Reduction in Wart Count at End of Study

Table 112 provides a summary of the ≥50% clearance rate at EOS for theIn population (overall and by gender). These data are shown graphicallyin FIG. 31.

TABLE 112 Proportion of Subjects with ≥50% Clearance at End of Study-ITTPopulation (LOCF) IMIQUIMOD CREAM 3.75% 2.5% PLACEBO (N = 195) (N = 178)(N = 97) ITT Population (LOCF) at EOS n/N^(a) (%) 99/195 (50.8) 61/178(34.3) 19/97 (19.6) 95% CI 43.5, 58.0 27.3, 41.7 12.2, 28.9 P value vsPlacebo <0.001** 0.015** — P value vs 2.5% Imiquimod <0.001** — — CreamMales n/N^(a) (%) 38/95 (40.0) 22/83 (26.5)  7/47 (14.9) 95% CI 30.1,50.6 17.4, 37.3 6.2, 28.3 P value vs Placebo   0.003** 0.136 — P valuevs 2.5% Imiquimod   0.066 — — Cream Females n/N^(a) (%) 61/100 (61.0)39/95 (41.1) 12/50 (24.0) 95% CI 50.7, 70.6 31.1, 51.6 13.1, 38.2 Pvalue vs Placebo <0.001** 0.053 — P value vs 2.5% Imiquimod   0.005** —— Cream LOCF = last observation carried forward, 95% CI= 95% confidenceinterval. ^(a)n/N = number of subjects with complete clearance at end ofstudy divided by the number of subjects analyzed 50% clearance wasdefined as at least a 50% reduction in the number of warts in thetreatment area compared with Baseline. P values are fromCochran-Mantel-Haenszel test, stratified by gender and analysis site(overall population) or stratified by analysis site (gender subgroups),taking 2 treatment groups at a time. The P values marked with ** arestatistically significant using Hochberg's modified Bonferroniprocedure. Confidence intervals were calculated using the exactbinominal statistics.

In the overall ITT population, the rate of ≥50% clearance of EGW at EOSwas significantly higher in the active treatment groups compared withplacebo, and in the 3.75% imiquimod group compared with 2.5% imiquimod.In both the male and female subgroups, the ≥50% clearance rate issignificantly higher with 3.75% imiquimod than with placebo, but therewas no significant difference between 2.5% imiquimod and placebo. Therewas a significant difference between 3.75% and 2.5% imiquimod forfemales but not for males. In all treatment groups, the ≥50% clearancerates at EOS were higher in females than in males.

Results were similar in the PP population. In the overall PP population,the rate of ≥50% clearance of EGW at EOS was significantly higher in theactive treatment groups compared with placebo, and in the 3.75%imiquimod group compared with 2.5% imiquimod. In both the male andfemale subgroups, the ≥50% clearance rate is significantly higher with3.75% imiquimod than with placebo. There was a significant differencebetween 2.5% imiquimod and placebo, and between 3.75% and 2.5% imiquimodfor females but not for males. In all treatment groups, the ≥50%clearance rates at EOS were higher in females than in males.

Subjects with ≥50% Reduction in Wart Count at End of Treatment

Table 113 provides a summary of the ≥50% clearance rate at EOT for theITT population (overall and by gender).

TABLE 113 Proportion of Subjects with >50% Clearance at End ofTreatment-ITT Population (LOCF) IMIQUIMOD CREAM 3.75% 2.5% PLACEBO ITTPopulation (LOCF) at EOT n/N^(a) (%) 93/195 (47.7) 58/178 (32.6) 15/97(15.5) 95% CI 40.5, 54.9 25.8, 40.0 8.9, 24.2 P value vs Placebo<0.001** 0.004** — P value vs 2.5% Imiquimod   0.002** — — Cream Malesn/N^(a) (%) 36/95 (37.9) 20/83 (24.1)  7/47 (14.9) 95% CI 28.1, 48.415.4, 34.7 6.2, 28.3 P value vs Placebo   0.007** 0.299 — P value vs2.5% Imiquimod   0.050** — — Cream Females n/N^(a) (%) 57/100 (57.0)38/95 (40.0)  8/50 (16.0) 95% CI 46.7, 66.9 30.1, 50.6 7.2, 29.1 P valuevs Placebo <0.001** 0.003** — P value vs 2.5% Imiquimod   0.017** — —Cream LOCF = last observation carried forward, 95% CI = 95% confidenceinterval. ^(a)n/N = number of subjects with complete clearance at end ofstudy divided by the number of subjects analyzed 50% clearance wasdefined as at least a 50% reduction in the number of warts in thetreatment area compared with Baseline. P values are fromCochran-Mantel-Haenszel test, stratified by gender and analysis site(overall population) or stratified by analysis site (gender subgroups),taking 2 treatment groups at a time. The P values marked with ** arestatistically significant using Hochberg's modified Bonferroniprocedure. Confidence intervals were calculated using the exactbinominal statistics.

In the overall ITT population, the rate of ≥50% clearance of EGW at EOTwas significantly higher in the active treatment groups compared withplacebo, and in the 3.75% imiquimod group compared with 2.5% imiquimod.In both the male and female subgroups, the ≥50%® clearance rate wassignificantly higher with 3.75% imiquimod than with placebo and with3.75% imiquimod than with 2.5% imiquimod. There was a significantdifference between 2.5% imiquimod and placebo for females but not formales. In all treatment groups, the ≥50% clearance rates at EOT werehigher in females than in males.

Results were similar in the PP population. In the overall PP population,the rate of ≥50% clearance of EGW at EOT was significantly higher in theactive treatment groups compared with placebo, and in the 3.75%imiquimod group compared with 2.5% imiquimod. In both the male andfemale subgroups, the ≥50% clearance rate was significantly higher with3.75% imiquimod than with placebo, and was significantly higher with2.5% imiquimod versus placebo in females but not males. There was nosignificant difference between 3.75% and 2.5% imiquimod in either gendersubgroup.

Subjects with ≥50% Reduction in Wart Count by Analysis Week

As shown in FIG. 32 for the overall ITT population, the differencebetween each of the imiquimod treatment groups and placebo wasstatistically significant at Week 16 (P<0.001 for 3.75% imiquimod vsplacebo; P=0.015 for 2.5% imiquimod vs placebo), and at allpost-Baseline assessment time points, with the exception of Week 2 inthe 2.5% imiquimod group. The ≥50% clearance rate in the 3.75% imiquimodgroup was significantly higher than that in the 2.5% imiquimod treatmentgroup at End of Study (LOCF) (P<0.001) and at all assessment time pointsafter the Week 2 assessment.

The ≥50% clearance rates were statistically significantly higher in the3.75% imiquimod group compared with placebo at Week 4 and thereafter inboth genders. The differences between 2.5% imiquimod and placebo weresignificant at Weeks 4 and 6 in males, and at Weeks 6, 8, 10, and 14 infemales.

Results in the PP population were similar to those in the ITTpopulation. Compared with placebo, the ≥50% clearance rate wassignificantly higher in the 3.75% imiquimod group at all analysis timepoints after Week 0, and was significantly higher with 2.5% imiquimod atall analysis time points except Weeks 12 and 14.

Wart Counts and Change and Percent Change from Baseline in Wart Counts

Summaries of the EGW counts, change from Baseline in EGW counts, andpercent change from Baseline in EGW counts over the course of the studyare presented in Table 114 for the overall ITT population. The meanpercent changes in EGW count over time are presented graphically in FIG.33 for the ITT population.

TABLE 114 Summary of External Genital Wart Count from Baseline to End ofTreatment and End of Study-ITT Population (LOCF) Imiquimod Cream 3.75%2.5% Placebo (N = 195) (N = 178) (N = 97) Baseline Mean (SD)    8.6(6.4)    9.2 (6.7)   11.6 (8.8) Median    7    7    8 Min, Max 2, 30 2,30 2, 30 P value vs Placebo <0.001**    0.009** — P value vs 2.5%Imiquimod    0.347 — — End of Treatment (Week 8) Mean (SD)    4.8 (5.7)   7.1 (7.5)   10.4 (9.6) Median    3    5    7 Min, Max 0, 30 0, 44 0,43 End of Study/Week 16 Mean (SD)    4.5 (5.8)    6.8 (7.6)   10.1 (9.9)Median    3    5    7 Min, Max 0, 30 0, 47 0, 43 Change from Baseline toEOS Mean (SD)  −4.1 (5.6)  −2.4 (5.8)   −1.5 (6.4) Median  −9  −1    0Min, Max −29, 7 −22, 21 −28, 15 P value vs Placebo  <0.001**    0.021**P value vs 2.5% Imiquimod  <0.001** — Percent Change from Baseline toMean (SD) −45.8 (47.3) −26.6 (55.8)   −9.4 (57.0) Median −50.0 −14.6   0.0 Min, Max −100, 100 −100, 222 −100, 350 P value vs Placebo <0.001**    0.008** — P value vs 2.5% Imiquimod  <0.001** — — P valuesare from Cochran-Mantel-Haenszel test, stratified by gender and analysissite, taking 2 treatment groups at a time. Change from Baseline iscalculated as the post-Baseline value minus the Baseline value. Changefrom Baseline P values are from analysis of covariance (ANCOVA),controlling for Baseline wart count, gender, and analysis site. The Pvalues marked with ** are statistically significant using Hochberg'smodified Bonferroni procedure.

The mean EGW count at Baseline was significantly lower in the activetreatment groups compared with placebo at Baseline for the overall ITTpopulation. At both EOT and EOS, the EGW counts were lowest n the 3.75%imiquimod group and highest in the placebo group. At EOS, the meanchange from Baseline in EGW count was significantly greater in theactive treatment groups compared with placebo, and was significantlygreater in the 3.75% imiquimod group compared with 2.5% imiquimod.

In the gender subgroups, the Baseline EGW counts were significantlylower in the 3.75% imiquimod group compared with placebo for females,and were significantly lower in both active treatment groups comparedwith placebo in males. The mean change and mean percent change fromBaseline at BUS in EGW count was significantly larger for 3.75%imiquimod versus placebo in males and in females. The mean percentchange from Baseline at EOS in EGW count was significant for 2.5%imiquimod versus placebo only in females.

As shown in FIG. 33 for the overall ITT population, the mean percentdecrease from Baseline in wart count in the 3.75% imiquimod treatmentgroup was consistently larger than that with 2.5% imiquimod or placebo,and the differences were statistically significant at all post-Baselineanalysis time points. The mean percent decrease in the 2.5% imiquimodgroup was larger compared with placebo, and the difference wasstatistically significant at Weeks 4, 6, 12, 14, and 16.

For the PP population, summaries of the EGW counts, change from Baselinein EGW counts, and percent change from Baseline in EGW counts over thecourse of the study are presented in Table 115.

TABLE 115 Summary of External Genital Wart Count from Baseline to End ofTreatment and End of Study-PP Population (Observed Cases) IMIQUIMODCREAM 3.75% 2.5% PLACEBO Baseline N   137   133   76 Mean (SD)    8.7(6.4)    9.1 (6.5)   11.6 (8.8) Median    7    8    9 Min, Max 2, 30 2,30 2, 30 P value vs Placebo  <0.001**    0.005** — P value vs 2.5%   0.540 — — Imiquimod End of Treatment (EOT) N   137   134   76 Mean(SD)    4.2 (5.4)    6.3 (7.5)   10.6 (9.7) Median    3    4    7 Min,Max 0, 30 0, 44 0, 43 End of Study (EOS) N   137   134   76 Mean (SD)   3.8 (5.5)    5.9 (7.7)   10.4 (10.0) Median    2    4    7 Min, Max0, 30 0, 47 0, 43 Change from Baseline at EOS N   137   134   76 Mean(SD)  −4.9 (6.0)  −3.1 (6.4)  −1.2 (6.9) Median  −3  −2  0 Min, Max −29,7 −22, 21 −28.15 P value vs Placebo  <0.001**   <.001** — P value vs2.5%    0.015** — — Imiquimod Percent Change from Baseline at EOS N  137   134   76 Mean (SD) −54.0 (48.5) −34.4 (60.6)  −5.2 (61.1) Median −66.7  −38.8    0.0 Min, Max −100, 100 −100, 222 −100, 350 P value vsPlacebo  <0.001**  <0.001** — P value vs 2.5%    0.16** — — Imiquimod Pvalues are from Cochran-Mantel-Haenszel test, stratified by gender andanalysis site, taking 2 treatment groups at a time. Change from Baselineis calculated as the post-Baseline value minus the Baseline value.Change from Baseline P values are from analysis of covariance (ANCOVA),controlling for Baseline wart count, gender, and analysis site. The Pvalues marked with ** are statistically significant using Hochberg'smodified Bonferroni procedure.

The mean EGW count at Baseline was significantly lower in the activetreatment groups compared with placebo at Baseline for the PPpopulation, At both EOT and EOS, the EGW counts were lowest in the 3.75%imiquimod group and highest in the placebo group in the PP population.At EOS, the mean change from Baseline in EGW count was significantlygreater in the active treatment groups compared with placebo, and wassignificantly greater in the 3.75% imiquimod group compared with 2.5%imiquimod.

In both genders, the mean change and mean percent change from Baselinein EGW count at EOS was significantly larger in both active treatmentgroups compared with placebo, and there was no significant differencebetween the active treatment groups. At EOS, both the mean change andmean percent change from Baseline in EGW counts were significantlylarger in the active treatment groups compared with placebo.

The mean percent decrease from Baseline in wart count in the 3.75%imiquimod treatment group was consistently larger than that with 2.5%imiquimod or placebo. The differences between 3.75% imiquimod andplacebo were statistically significant at all post-Baseline assessmenttime points, while the differences between 3.75% and 2.5% imiquimod weresignificant at Weeks 2, 6, 8, EOT, 12, and EOS. The mean percentdecrease in the 2.5% imiquimod group was larger than that with placebo,but the difference was statistically significant only at EOT and EOS.

Time to Complete Clearance

Summaries of the time to complete clearance are shown in Table 116 forthe ITT population.

TABLE 116 Time to Clearance (days) for the ITT population ImiquimodCream 3.75% 2.5% Placebo (N = 195) (N = 178) (N = 97) All SubjectsKaplan-Meier N 195 178 97 1^(st) Quartile 58.0 117.0 >58 Median time tocomplete >71 >102 >112 clearance (2^(nd) quartile) 3rdQuartile >113 >113 >113 P value vs Placebo <0.001 0.035 — P value vs2.5% imiquimod cream 0.052 — Only Subjects Who Attained Clearance N 5334 10 1^(st) Quartile 31.0 32.0 51.0 Median time to complete 52.0 56.567.0 clearance (2″ Quartile) 3^(rd) Quartile 58.0 76.0 106.0 P valuesare from the log rank test comparing survival curves in the Kaplan-Meierframework, taking 2 treatment groups at a time.

Although the time to complete clearance in the ITT treatment groups wasnot reached, the median time to clearance was statisticallysignificantly shorter in the 3.75% imiquimod group compared with placebo(P<0.001 using the log-rank test) and in the 2.5% imiquimod groupcompared with placebo (P=0.035). The difference between the 2 imiquimodtreatment groups approached statistical significant (P=0.052).

For those subjects who attained complete clearance, the median time tocomplete clearance was 52 days in the 3.75% imiquimod group, 56 days inthe 2.5% imiquimod group, and 67 days in the placebo group.

Results in the PP population were similar to those in the ITTpopulation, Among the subset of subjects who achieved complete clearancein the PP population, the median time to clearance was 57 days in the3.75% imiquimod group, 56.5 days in the 2.5% imiquimod group, and 72days in the placebo group.

Complete clearance was achieved more rapidly in female subjects comparedwith males in both the ITT and PP populations.

Sustained Complete Clearance Rate at Week 12 of the Follow-Up forRecurrence Period

The numbers of subjects who remained clear in the follow-up period orwho had a recurrence of EGW are presented in Table 117.

TABLE 117 Wart Recurrence Rate-Follow-up for Recurrence Population(LOCF) Imiquimod Cream 3.75% 2.5% Placebo (N = 49) (N = 31) (N = 6)Recurrence Follow-up- Subjects who remained clear^(a), n/N 37/49 (75.5)15/31 (48.4) 5/6 (83.3) Subjects who had a recurrence, n/N  7/49 (14.3) 6/31 (19.4) 0 Missing  5/49 (10.2) 10/31 (32.3) 1/6 (16.7) 95%Confidence interval 5.9, 27.2 7.5, 37.5 — ^(a)Includes those who had avisit within window with no warts.

Thirty-seven subjects (75.5%) in the 3.75% imiquimod group, 15 subjects(48.4%) in the 2.5% imiquimod group, and 5 subjects (83.3%) in theplacebo group achieved complete clearance at EOS that was sustainedthroughout the 12-week follow-up period. Data were missing for 5subjects (10.2%) in the 3.75% imiquimod group, 10 subjects (32.3%) inthe 2.5% imiquimod group, and 1 subject (16.7%) in the placebo group sotheir recurrence status was not known, but at least 14.3% of the 3.75%imiquimod group and 19.4% of the 2.5% imiquimod group in the follow-upfor recurrence population are known to have shown recurrence of EONwithin 12 weeks of the initial clearance.

Statistical/Analytical Issues

Adjustments for Covariates

The primary efficacy analysis was based on a CMH test, stratified bygender and analysis site. Secondary analyses were performed in a numberof subgroups. No other adjustments for covariates were planned.

Handling of Dropouts or Missing Data

For the primary In analysis, missing observations due to earlydiscontinuation were imputed using the LOCF. Screening data were carriedforward if no baseline data existed for the subject—Baseline data werecarried forward if no post-baseline data existed for the subject.Additional analyses of the primary efficacy variable were performed inwhich (1) all missing observations were considered as failures and (2)using only observed cases, without imputations. The results of theseadditional analyses are presented in Table 118 below.

TABLE 118 Proportion of Subjects with Complete Clearance at End of Study(Sensitivity and Supporting Analyses)-ITT Population Imiquimod Cream3.75% 2.5% Placebo (N = 195) (N = 178) (N = 97) ITT Population (allsubjects with missing data were counted as failures) n/N^(a) (%) 53/195(27.2) 34/178 (19.1) 10/97 (10.3) 95% CI 21.1, 34.0 13.6, 25,7 5.1, 18.1P value vs Placebo <0.001 **   0.065 — P value vs 2.5%   0.061 — —Imiquimod Cream ITT Population (observed cases) n/N^(a) (%) 53/195(27.2) 34/178 (19.1) 10/97 (10.3) 95% CI 21.1, 34.0 13.6, 25.7 5.1, 18.1P value vs Placebo <0.001**   0.065 — P value vs 2.5%   0.061 — —Imiquimod Cream 95% CI = 95% confidence interval. ^(a)n/N = number ofsubjects with complete clearance at end of study divided by the numberof subjects analyzed. P values are from Cochran-Mantel-Haenszel test,stratified by gender and analysis site, taking 2 treatment groups at atime. P-values marked with ** are statistically significant usingHochberg's modified Bonferroni procedure. Confidence intervals werecalculated using the exact binomial distribution.

Results of these additional analyses are identical to those obtainedbased upon LOCF for all treatment groups.

Multicenter Studies

In order to obtain at least 6 subjects per site per active treatmentgroup, investigational sites yielding fewer than 15 subjects werecombined in order of geographic proximity. The exact composition ofthese “analysis sites” was determined and documented prior to breakingthe study blind. The stratification for CMH analyses was based on theanalysis sites, not on the actual investigational sites.

Multiple Comparison/Multiplicity

The primary efficacy endpoint, complete clearance rate at the End ofStudy, was analyzed using Cochran-Mantel-Haenszel (CMH) statistics,stratifying on gender and site. All pairwise comparisons of activetreatment versus placebo were made using Hochberg's modified Bonferroniprocedure. If either test was significant at a 0.025 level ofsignificance, then that test was considered significant. Otherwise, ifboth tests were significant at 0.05, then both tests were consideredsignificant. The 3.75% and 2.5% treatment groups were compared to eachother at the 0.05 level of significance if at least one of thesetreatment groups was found to be different than the placebo using theHochberg's test.

The 4 secondary efficacy variables were to be tested hierarchicallyusing Hochberg's modified Bonferroni procedure to conserve Type 1 error.First, only if the primary endpoint showed statistical significant couldthe first secondary efficacy variable be tested. If the prior secondaryefficacy variable showed statistical significance then the nextsecondary efficacy variable could be tested, etc.

Use of an “Efficacy Subset” of Subjects

Efficacy variables were analyzed for a Per Protocol (PP) subset ofsubjects. The PP population included all subjects in the ITT populationwho had no major protocol violations: 137 subjects in the 3.75%imiquimod treatment group, 134 subjects in the 2.5% imiquimod treatmentgroup, and 76 subjects in the placebo group. The demographic andbaseline characteristics in the PP population were similar to those inthe ITT population, although the mean total wart area was slightly lessin the 3.75% imiquimod group, and slightly greater in the 2.5% imiquimodand placebo groups for the PP population.

In the analysis of the primary efficacy variable, the results in the PPpopulation were similar to those in the ITT population. The proportionof subjects with complete clearance at Week 16/EOS was statisticallysignificantly greater in the 3.75% imiquimod treatment group than in theplacebo group; and larger but not significantly greater than in the 2.5%imiquimod group. While the complete clearance rate with 2.5% imiquimodwas larger than that with placebo, the difference was statisticallysignificant only in the analyses of the PP population.

Results in the PP population for the other efficacy variables were alsosimilar to those from the ITT population.

Examination of Subgroups

The primary efficacy variable was summarized by investigator site, byanalysis site, by investigator medical specialty, by gender, by agesubgroup, by race subgroup, by baseline EGW count subgroup, by baselinewart areas, by anatomic locations (inguinal, perineal, perianal, glanspenis, penis shaft, scrotum, foreskin, or vulva), by number of anatomiclocations affected by EGW (ie, one location versus multiple), by whetherfirst EGW episode, by duration from first diagnosis of EGW, by restperiods (yes or no), and by previous treatment with imiquimod (yes orno).

In general, the complete clearance rates increased in a dose-dependentmanner regardless of subgroup. The most striking subgroup effect wasobserved in the analysis by gender. The complete clearance rates wereconsistently higher in females than in males in all treatment groups.Complete clearance at EOS was attained by 20.0%, 13.3%, and 4.3% of malesubjects and by 34.0%, 24.2%, and 16.0% of female subjects in the 3.75%imiquimod, 2.5% imiquimod, and placebo groups, respectively.

The complete clearance rates tended to be higher in the followingsubgroups:

-   -   Females;    -   Lower baseline wart count (≤7 compared with >7);    -   More recent first EGW diagnosis (≤1 year compared with >1 year);    -   Subjects with baseline warts in the perineal area, the perianal        area, on the foreskin, or on the vulva;    -   Subjects who took a rest period (noted in the imiquimod groups        but not placebo);    -   No previous imiquimod treatment (noted in the imiquimod groups        but not placebo).

In the 3.75% imiquimod group only, the complete clearance rate washigher in older subjects (>35 years) compared with younger subjects, andin baseline wart areas >70 and ≤150 mm² compared with baseline wartareas ≤70 mm² or >150 mm².

When analyzed by analysis site or investigative site subgroups, thecomplete clearance rate was highest in the 3.75% imiquimod group at14/20 analysis sites and 17/30 investigational sites. When analyzed byinvestigator site specialty subgroups, the highest overall completeclearance rates were observed at sites specializing in gynecology orfamily/general practice, where more female subjects were enrolled. Atsites specializing in dermatology, gynecology, or familypractice/general practice, the complete clearance rates increased in adose-dependent manner. Few subjects in any treatment group attainedcomplete clearance in sites specializing in urology (sites at which onlymale subjects were enrolled) or infectious disease.

Additional Analyses by Gender

Additional analyses of the data were performed to explore the possibleeffect of gender on efficacy. Of the 470 subjects randomized into thetrial, 225 (47.9%) were male and 245 (52.1%) were female. Similarpercentages of males and females completed the evaluation period. Lostto follow-up and subject's request were the most common reasons forstudy discontinuation in both genders, and similarly low proportions ofmales (0.4%) and females (2.0%) withdrew for safety reasons. The time tolost to follow-up was similar in the active treatment groups for bothgenders.

As in the overall population, the response with 3.75% imiquimod creamwas significantly superior to that with placebo in both genders. Thecomplete clearance rates were consistently higher in females comparedwith males in all treatment groups for both the ITT and PP populations,including the sensitivity and supporting analyses of the ITT population.

A summary of complete clearance of all anatomic sites at EOS by baselineinvolvement of anatomic locations is presented in Table 119, below. Ofnote, a majority of subjects of each gender had involvement of more thanone anatomic site at Baseline.

TABLE 119 Complete Clearance at End of Study by Baseline AnatomicLocation-ITT Population (LOCF) Imiquimod Cream Baseline 3.75% 2.5%Placebo anatomic location (N = 195) (N = 178) (N = 97) Both genders-n/N(%)^(a) Inguinal  9/46 (19.6)  5/31 (16.1) 1/19 (5.3) Perineal 21/55(38.2) 12/49 (24.5) 5/26 (19.2) Perianal 17/50 (34.0) 11/60 (18.3) 5/24(20.8) Males-n/N (%) Inguinal  5/29 (17.2)  5/20 (25.0) 1/13 (7.7)Perineal  1/7 (14.3)  0/6 (0.0)  0/4 (0.0) Perianal  1/6 (16.7)  0/8(0.0)  0/2 (0.0) Glans Penis  2/9 (22.2)  0/6 (0.0)  0/5 (0.0) PenisShall 14/77 (18.2) 11/71 (15.5) 2/42 (4.8) Scrotum  4/27 (14.8)  5/29(17.2)  0/8 (0.0) Foreskin  1/3 (33.3)  2/4 (50.0)  0/1 (0.0)Females-n/N (%) Inguinal  4/17 (23.5)  0/11 (0.0)  0/6 (0.0) Perineal20/48 (41.7) 12/43 (27.9) 5/22 (22.7) Perianal 16/44 (36.4) 11/52 (21.2)5/22 (22.7) Vulva 18/59 (30.5) 13/60 (21.7) 3/32 (9.4) ^(a)Subjects withcomplete clearance are included in the numerator.

In the anatomic areas common to both genders, perineal and perianalinvolvement was relatively common in females; few males had baselinedisease in those areas. Females with perineal or perianal EGW atBaseline demonstrated relatively high rates of complete clearance atEOS. The third common anatomic site, the inguinal area, was involved in27.6% of males and 13.9% of females at Baseline. The lowest clearancerates occurred in subjects with inguinal area involvement (at Baseline)in all treatment groups.

The anatomic areas most commonly affected with EGW at Baseline in maleswere the penis shaft, scrotum, and inguinal area. The complete clearancerates in subjects whose EGW included these areas at Baseline weresimilar for the 3.75% imiquimod and 2.5% imiquimod groups. In females,the vulva, perianal area, and perineal area were the areas most commonlyaffected with EGW at Baseline. The complete clearance rates were highestwith 3.75% imiquimod for all baseline anatomic areas in female subjects.

In both genders, complete clearance rates were higher in subjects whotook a rest period from imiquimod treatment compared with those who didnot take a rest period. The complete clearance rates in males werehigher for subjects >35 years of age than in younger subjects but no agetrend was observed in females. Females with a first EGW diagnosis withinone year and those experiencing their first EGW episode had higherclearance rates than those with a longer EGW history or with previousEGW outbreaks, but no trend was observed in males.

Exploratory Analysis of Anatomic Specific Complete Clearance

In this study, subjects applied study medication to individual warts invarious anatomic areas identified at Baseline. Some subjects developednew warts during the study. These new warts may have appeared withinanatomic areas already displaying EGW at Baseline and/or these warts mayhave appeared in ‘new’ anatomic areas that had not been exposed to studymedication at initiation of treatment. New warts were treated with studymedication when they appeared, but received less than a full course oftreatment, because treatment was not extended beyond 8 weeks fromrandomization.

An exploratory analysis of complete clearance within the specificanatomic areas affected with EGW at Baseline was performed for theoverall ITT population and by gender.

Drug Dose, Drug Concentration, and Relationships to Response

This study examined the efficacy of 2.5% imiquimod cream and 3.75%imiquimod cream, that was applied once daily for a maximum of 8 weeks.Subjects self-applied a maximum of 1 packet (250 mg) of study drug perapplication. No sample collection for pharmacokinetic determinations wasplanned in this study; therefore, no analysis of drug concentration wasdone.

A dose response was observed in this study. The 3.75% imiquimod creamconsistently demonstrated higher efficacy rates compared with the 2.5%imiquimod cream for all primary and secondary efficacy measures, in boththe ITT and PP populations. The difference between the 2 activetreatment groups was not statistically significant for the primaryefficacy analysis, but was significant for several secondary andtertiary efficacy variables.

Drug-Drug and Drug-Disease Interactions

No drug-drug interactions with respect to drug disposition and/ormetabolism were evaluated in the study.

Efficacy Conclusions

The investigational product 3.75% imiquimod cream met the criteria forefficacy as defined in this protocol. For the 2.5% imiquimod cream,efficacy measures were consistently higher than those for placebo, butthe values were not consistently significantly different compared withplacebo.

-   -   For the primary endpoint (the rate of complete clearance of EGW        at Week 16/E0S), results with the 3.75% imiquimod cream were        statistically significantly superior to results with the placebo        cream. This effect was observed in both the ITT and PP        populations, overall and in both genders. In the ITT population,        the rates of complete clearance were 27.2% and 19.1%,        respectively, in the 3.75% and 2.5% imiquimod treatment groups,        compared with 10.3% in the placebo group. Results in the 3.75%        imiquimod group were numerically but not statistically higher        than those in the 2.5% imiquimod group.    -   The complete clearance rate at end of treatment (EOT) was        statistically significantly superior with 3.75% imiquimod        compared with placebo and with 2.5% imiquimod overall and in the        female subgroup in both the ITT and PP populations.    -   Over the course of the study, the complete clearance rates were        significantly superior with 3.75% imiquimod compared with        placebo at every analysis time point after Week 2 in both the        ITT and PP populations. Results were significantly higher for        3.75% imiquimod vs 2.5% imiquimod at Weeks 8, 10, 12, and 14        (ITT population) and at Weeks 8, 12, and 14 (PP Population).    -   The partial (≥75%) clearance rate with the 3.75% imiquimod cream        was statistically significantly superior to the placebo cream at        Week 16/EOS for the ITT population (overall and in both        genders), and at Week 16 and EOS for, the PP population (overall        and in both genders). Results were significantly higher for        3.75% imiquimod vs placebo at all analysis time points after        Week 2 (ITT population) and Week 0 (PP population).    -   Over the course of the study, the partial (≥75%) clearance rates        were significantly superior with 3.75% imiquimod compared with        placebo at every analysis time point after Week 4 (ITT        population) and Week 2 (PP population). Results were        significantly higher for 3.75% imiquimod vs 2.5% imiquimod at        every time point after Week 4 in the ITT population.    -   The ≥50% clearance rate at EOS was significantly greater in the        3.75% imiquimod group compared with placebo in both the ITT and        PP populations, overall and in both genders. Results were        significant for 3.75% imiquimod versus 2.5% imiquimod at EOS        overall and in the female subgroup in the ITT and PP        populations.    -   Over the course of the study, the ≥50% clearance rates were        significantly superior with 3.75% imiquimod compared with        placebo at every analysis time point after Week 0 in both the        ITT and PP populations. Results were significantly higher for        3.75% imiquimod vs 2.5% imiquimod at all analysis time points        after Week 2 in the ITT population.    -   The complete and partial clearance rates were consistently        higher in the female subgroup compared with the male subgroup in        all treatment groups. Mean change and percent change from        Baseline in EGW counts were consistently higher in females        compared with males in the active treatment groups.    -   At EOS, the percent change from Baseline in wart count with, the        3.75% imiquimod cream was statistically significantly greater        than with placebo cream or with 2.5% imiquimod cream in both the        ITT and PP populations.    -   Although the median time to complete clearance for the ITT        treatment groups was not reached, the time to clearance was        statistically significantly shorter in the 3.75% imiquimod group        compared with placebo (P<0.001) and in the 2.5% imiquimod group        compared with placebo (P=0.035). For those subjects who attained        complete clearance, the median time to complete clearance was 52        days, 56.5 days, and 67 days for the 3.75% imiquimod, 2.5%        imiquimod, and placebo groups, respectively.    -   Thirty-seven of 49 subjects (75.5%) in the 3.75% imiquimod group        remained completely clear of EGW through the 12-week follow-up        period, while 7/49 subjects had wart recurrence and the status        is unknown for 5/49 subjects. Fifteen of 31 subjects (48.4%) in        the 2.5% imiquimod group (with 10 missing subjects), and 5 of 6        subjects in the placebo group (with 1 missing subject) remained        clear through the follow-up period. Thus, at least 75.5% of the        3.75% imiquimod group and 48.4% of the 2.5% imiquimod group in        the follow-up for recurrence population are known to have        sustained clearance of all anatomic sites for at least 12 weeks        from the initial clearance.        Safety Evaluation        Extent of Exposure

An overall summary of study drug exposure for the ITT population ispresented in Table 120. In this study, the ITT and safety populationsare identical.

TABLE 120 Overall Study Drug Exposure-ITT Population Imiquimod Cream3.75% 2.5% Placebo (N = 195) (N = 178) (N = 97) Treatment duration,days^(a)- All subjects N 167 145 87 Mean ± SD 47.8 (15.8) 50.2 (14.9)52.8 (12.1) Median 56 56 56 Min, Max 6, 78 6, 87 1, 70 Total number ofpackets used N 159 132 81 Mean ± SD 43.3 (16.1) 46.0 (13.2) 51.7 (10.8)Median 48 51 55 Min, Max 0, 64 6, 66 1, 63 Number of Days Treated ^(b) N167 145 87 Mean ± SD 43.1 (15.8) 44.3 (14.2) 50.3 (12.0) Median 48 49 54Min, Max 6, 69 6, 63 1, 67 Percent of Treatment Compliance^(c) N 182 16393 Mean ± SD 84.3 (25.0) 84.7 (25.0) 86.8 (23.8) Median 95 95 96 Min,Max 0, 127 16, 120 8, 111 SD-standard deviation, min = minimum,max-maximum. ^(a)Duration of treatment is date of last dose minus dateof first dose plus 1. Duration of treatment is missing if either thedate of first dose or the date of last dose is partial or missing. Lastdose is defined as last date on study medication. ^(b) Days treated isthe duration of treatment minus rest period days and missed doses.^(c)Based on either packet use compliance or treatment days compliancewhichever is greater.

The mean treatment duration, number of study medication packets used,and number of days treated were lowest in the 3.75% imiquimod treatmentgroup and highest in the placebo group.

Based on the available data, on average, the subjects used 43.3 packetsof 3.75% imiquimod, 46.0 packets of 2.5% imiquimod, and 51.7 packets ofplacebo. Mean treatment duration was 47.8 days in the 3.75% imiquimodtreatment group, 50.2 days in the 2.5% imiquimod treatment group, and52.8 days in the placebo group. When rest periods and missed doses weresubtracted, the numbers of treated days were reduced to 43.1, 44.3, and50.3 days—in the 3.75% imiquimod, 2.5% imiquimod, and placebo groups,respectively.

The mean number of packets used, number of days treated, and percenttreatment compliance were higher in the males than in females in theactive treatment groups in the ITT and safety populations. Meantreatment duration was higher in males than in females for the 3.75%imiquimod group. There was no difference between genders in the placebogroup.

Adverse Events (AEs)

Brief Summary of Adverse Events

A summary of the overall incidence of AEs is provided in Table 121 forthe safety population.

TABLE 121 Summary of Adverse Events-Safety Population Imiquimod 3.75%2.5% Placebo (N = 195) (N = 178) (N = 97) Subjects with any AE, n (%) 61(31.3) 55 (30.9) 25 (25.8) Number of AEs 146 124 43 Subjects with any:Treatment-related^(a) AE, n (%) 30 (15.4) 27 (15.2)  2 (2.1) SAE, n (%) 2 (1.0)  2 (1.1)  0 AEs of severe intensity, n (%) 10 (5.1) 12 (6.7)  1(1.0) AE leading to study  3 (1.5)  2 (1.1)  1 (1.0) discontinuation, n(%) AE = adverse event, SAE = serious adverse event ^(a)Includes“Probably related” and “Related” AEs. Counts reflect numbers of subjectsin each treatment group reporting one or more adverse events that map tothe MedDRA system organ class. A subject may be counted once only ineach row of the table. A treatment-emergent AE is an AE that began orworsened in severity after Day 1 and no more than 30 days after the lastapplication of study drug.

The number of subjects who experienced any AE (including those notconsidered treatment emergent) was similar in the active treatmentgroups (31.3% and 30.9% in the 3.75% and 2.5% imiquimod groups,respectively) and slightly lower in the placebo group (25.8%). Thenumber of subjects with AEs considered treatment related or severe inintensity was similar in the active treatment groups and lower in theplacebo group. The number of subjects with an SAE or who withdrew fromthe study due to an AE was low in all treatment groups.

An overall summary of the incidence of treatment-emergent AEs isprovided in Table 122 for the safety population.

TABLE 122 Summary of Treatment-Emergent Adverse Events-Safety PopulationIMIQUIMOD CREAM 3.75% 2.5% PLACEBO (N = 195) (N = 178) (N = 97) Subjectswith any AE, n (%) 53 (27.2) 52 (29.2) 22 (22.7) Number of AEs 123 10236 Subjects with any: Treatment-related^(a) AE, n (%) 30 (15.4) 27(15.2)  2 (2.1) SAE, n (%)  1 (0.5)  2 (1.1)  0 AEs of severe intensity,n (%)  7 (3.6) 11 (6.2)  1 (1.0) AE leading to study  3 (1.5)  2 (1.1) 1 (1.0) Discontinuation, n (%)   Subjects with any application 29(14.9) 25 (14.0)  2 (2.1) Site reaction, n (%) AE = adverse event, SAE =serious adverse event ^(a)Includes “Probably related” and “Related” AEs.Counts reflect numbers of subjects in each treatment group reporting oneor more adverse events that map to the MedDRA system organ class. Asubject may be counted once only in each row of the table. Atreatment-emergent AE is an AE that began or worsened in severity afterDay 1 and no more than 30 days after the last application of study drug.

The number of subjects with treatment-emergent AEs was similar in theactive treatment groups (27.2% and 29.2% in the 3.75% and 2.5% imiquimodgroups, respectively) and slightly lower in the placebo group (22.7%).The number of subjects with treatment-emergent AEs considered treatmentrelated or severe in intensity was similar in the active treatmentgroups and lower in the placebo group. A higher percentage of subjectsin the active treatment groups had application site reactions comparedwith placebo. The number of subjects with an SAE or who withdrew fromthe study due to an AE was low in all treatment groups.

Most Frequent Adverse Events

A treatment-emergent AE was defined as an AE that began or worsened inseverity after the first application of the study drug and no more than30 days after the last application of the study drug. The incidence ofthe most commonly-occurring treatment-emergent AEs is presented bypreferred term in Table 123.

TABLE 123 Number (%) of Subjects with Most Frequent Treatment-EmergentAdverse Events (≥1% in any active treatment group)-Safety PopulationIMIQUIMOD CREAM 3.75% 2.5% PLACEBO (N = 195) (N = 178) (N = 97) Subjectswith any treatment-emergent 53 (27.2) 52 (29.2) 22 (22.7) AE, n (%)Subjects with any AE, n (%) Application site pain 11 (5.6) 12 (6.7)  1(1.0) Application site irritation 12 (6.2)  5 (2.8)  1 (1.0)Nasopharyngitis  7 (3.6)  7 (3.9)  3 (3.1) Application site pruritus  3(1.5)  3 (1.7)  1 (1.0) Application site reaction  3 (1.5)  3 (1.7)  0Back pain  2 (1.0)  3 (1.7)  1 (1.0) Vaginitis bacterial  4 (2.1)  2(1.1)  0 Application site discharge  3 (1.5)  2 (1.1)  0 Applicationsite erythema  3 (1.5)  2 (1.1)  0 Upper respiratory tract infection  2(1.0)  2 (1.1)  1 (1.0) Pyrexia  2 (1.0)  1 (0.6)  1 (1.0) Applicationsite erosion  2 (1.0)  1 (0.6)  0 Application site oedema  2 (1.0)  1(0.6)  0 Ear infection  2 (1.0)  1 (0.6)  0 Headache  3 (1.5)  0  0Influenza  2 (1.0)  1 (0.6)  0 Vaginal candidiasis  0  2 (1.1)  1 (1.0)Application site bleeding  2 (1.0)  0  0 Application site excoriation  2(1.0)  0  0 Application site rash  2 (1.0)  0  0 Application site ulcer 2 (1.0)  2 (1.1)  0 Rash  2 (1.0)  0  0 Urinary tract infection  0  2(1.1)  0 AE = adverse event Counts reflect numbers of subjects in eachtreatment group reporting one or more adverse events that map to theMedDRA system organ class. A subject may be counted once only in eachrow of the table. A treatment-emergent AE is an AE that began orworsened in severity after the first application of the study drug andno more than 30 days after the last application of the study drug.

The AE reported with the greatest overall incidence was application sitepain, reported in 5.6% of subjects in the 3.75% imiquimod group, 6.7% ofsubjects in the 2.5% imiquimod group, and 1.0% of subjects in theplacebo group.

Application site irritation occurred with a higher frequency in the3.75% imiquimod group (6.2%) compared with the 2.5% imiquimod (2.8%) andplacebo (1.0%©) groups. With this exception, the incidence of theindividual AEs was similar in the 2 active treatment groups and lower inthe placebo group.

Flu-like symptoms and certain other systemic effects have been reportedwith 5% imiquimod treatment. The incidence of these AEs was very low inthe current study. These events were reported in this study in the 3.75%imiquimod, 2.5% imiquimod, and placebo groups, respectively, as follows:

-   -   pyrexia was reported in 2 (1.0%), 1 (0.6%), and 1 (1.0%)        subjects;    -   nausea was reported in 1 (0.5%), 1 (0.6%), and 1 (1.0%©)        subjects;    -   chills were reported in 0, 1 (0.6%), and 0 subjects;    -   influenza-like illness was reported in 1 (0.5%), 0, and 0        subjects;    -   myalgia was reported in 1 (0.5%), 0, and 0 subjects.        Adverse Events by System Organ Class

The incidence of AEs is presented by system organ class in Table 124.

TABLE 124 Number (%) of Subjects with Treatment-Emergent Adverse Eventsby System Organ Class-Safety Population IMIQUIMOD CREAM 3.75% 2.5%PLACEBO (N = 195) (N = 178) (N = 97) General disorders andadministration site conditions 30 (15.4) 26 (14.6)  3 (3.1) Infectionsand infestations 22 (11.3) 17 (9.6) 11 (11.3) Musculoskeletal andconnective tissue disorders  6 (3.1)  4 (2.2)  2 (2.1) Gastrointestinaldisorders  3 (1.5)  5 (2.8)  3 (3.1) Injury, poisoning and proceduralcomplications  3 (1.5)  5 (2.8)  1 (1.0) Skin and subcutaneous tissuedisorders  5 (2.6)  3 (1.7)  0 Nervous system disorders  4 (2.1)  2(1.1)  1 (1.0) Reproductive system and breast disorders  4 (2.1)  2(1.1)  1 (1.0) Respiratory, thoracic and mediastinal disorders  1 (0.5) 3 (1.7)  3 (3.1) Psychiatric disorders  0  1 (0.6)  2 (2.1) Renal andurinary disorders  1 (0.5)  1 (0.6)  0 Blood and lymphatic systemdisorders  0  1 (0.6)  0 Cardiac disorders  0  1 (0.6)  0 Eye disorders 0  0  1 (1.0) Immune system disorders  0  0  1 (1.0) Investigations  0 1 (0.6)  0 Surgical and medical procedures  0  1 (0.6)  0 AE = adverseevent Counts reflect numbers of subjects in each treatment groupreporting one or more AEs that map to the MedDRA system organ class. Asubject was counted only once in each row of the table.

General disorders and administration site conditions, as well asinfections and infestations, were the only system organ classes in whichAEs were reported with an incidence of ≥5% in at least one treatmentgroup.

Adverse Events by Intensity

Most of the AEs were of mild or moderate intensity. Two AEs were ratedas severe in at least 2 subjects: application site pain, reported in 2subjects (1.0%) in the 3.75% imiquimod treatment group, 3 subjects(1.7%) in the 2.5% imiquimod group, and 0 placebo subjects; andapplication site reaction, reported in 1 subject (0.5%) in the 3.75%imiquimod group, 2 subjects (1.1%) in the 2.5% imiquimod group, and 0placebo subjects.

Adverse Events by Relationship to Treatment

Treatment-emergent AEs are summarized by treatment group andrelationship to study treatment in Table 125.

TABLE 125 Number (%) of Subjects with Treatment-Emergent Adverse EventsRelated to Treatment-Safety Population IMIQUIMOD CREAM 3.75% 2.5%PLACEBO (N = 195) (N = 178) (N = 97) Subjects with any 30 (15.4) 27(15.2) 2 (2.1) treatment-related AE, n (%) Subjects with any treatmentrelated: SAE, n (%)  0  0 0 AE of severe intensity, n (%)  3 (1.5)  6(3.4) 0 AE leading to study  2 (1.0)  2 (1.1) 0 discontinuation, n (%)Application site pain 11 (5.6) 12 (6.7) 1 (1.0) Application siteirritation 12 (6.2)  5 (2.8) 1 (1.0) Application site pruritus  3 (1.5) 3 (1. ) 1 (1.0) Application site reaction  3 (1.5)  3 (1.7) 0Application site discharge  3 (1.5)  2 (1.1) 0 Application site erythema 3 (1.5)  2 (1.1) 0 Application site erosion  2 (1.0)  1 (0.6) 0Application site oedema  2 (1.0)  1 (0.6) 0 Application site bleeding  2(1.0)  0 0 Application site excoriation  2 (1.0)  0 0 Application siterash  2 (1.0)  0 0 Pyrexia  1 (0.5)  1 (0.6) 0 Application sitedermatitis  0  1 (0.6) 0 Application site discomfort  0  1 (0.6) 0Application site ulcer  0  1 (0.6) 0 Chills  0  1 (0.6) 0 Pain  1 (0.5) 0 0 Swelling  1 (0.5)  0 0 Deriztal cyst  1 (0.5)  0 0 Pruritus  1(0.5)  0 0 Rash  1 (0.5)  0 0 Skin discolouration  0  1 (0.6) 0Application site cellulitis  1 (0.5)  0 0 Vaginitis bacterial  0  1(0.6) 0 Excoriation  0  1 (0.6) 0 Dysuria  1 (0.5)  0 0 AE = adverseevent Counts reflect numbers of subjects in each treatment groupreporting one or more AEs that map to the MedDRA system organ class. Asubject was counted only once in each row of the table.Treatment-related includes Probably Related and Related.

Adverse events considered to be treatment related were reported in 30subjects (15.4%) in the 3.75% imiquimod treatment group, 27 subjects(15.2%) in the 2.5% imiquimod treatment group, and 2 subjects (2.1%) inthe placebo group. The most frequently reported treatment-related AEswere application site pain and application site irritation. Applicationsite adverse events were the only treatment-related AEs that occurred inmore than 1 subject in any treatment group. Application site pain,application site irritation, and application site pruritus, each in 1subject (1.0%), were the only treatment-related AEs reported in theplacebo group.

Treatment-related AEs of severe intensity were reported by 3 subjects inthe 3.75% imiquimod group and 6 subjects in the 2.5% imiquimod group.All were application site AEs and all resolved without sequelae. In the3.75% imiquimod group, 2 subjects had severe application site pain, and1 subject discontinued the study due to a severe application sitereaction. In the 2.5% imiquimod group, 2 subjects had severe applicationsite pain, 1 subject had a severe application site reaction, 1 subjecthad a severe application site irritation, 1 subject had both severeapplication site pain and reaction and discontinued the study, and 1subject discontinued the study due to severe application sitedermatitis.

Adverse Events by Subgroup

Treatment-emergent AEs were analyzed by gender, by age, by number ofanatomic areas affected by EGW, and by baseline wart count. As in theoverall population, application site reactions were the mostcommonly-reported AEs and treatment-related AEs in all subgroups for alltreatment groups.

Adverse Events by Gender

Summaries of the analysis by gender are provided in Table 126.

TABLE 126 Treatment-emergent Adverse Events by Gender-Safety PopulationMale Female 3.75% 2.5% 3.75% 2.5% Imiquimod Imiquimod Placebo ImiquimodImiquimod Placebo n = 95 n = 83 n = 47 n = 100 n = 95 n = 50 Subjectswith any AE, n (%) 22 (23.2) 18 (21.7)  9 (19.1) 31 (31.0) 34 (35.8) 13(26.0) Number of AEs 48 33 10 75 69 26 Number (%) of subjects with: .Any Treatment-related AE 12 (12.6) 10 (12.0) 1 (2.1) 18 (18.0) 17 (17.9)1 (2.0) Any SAE 0 (0.0) 1 (1.2) 0 (0.0) 1 (1.0) 1 (1.1) 0 (0.0) AnySevere AE 0 (0.0) 3 (3.6) 0 (0.0) 7 (7.0) 8 (8.4) 1 (2.0) Any AE leadingto Study 0 (0.0) 1 (1.2) 0 (0.0) 3 (3.0) 1 (1.1) 1 (2.0) DiscontinuationAny Application Site 12 (12.6) 10 (12.0) 1 (2.1) 17 (17.0) 15 (15.8) 1(2.0) Reaction

The overall incidence of treatment-emergent AEs was higher in femalesthan in males in all treatment groups. Treatment-related AEs, severeAEs, and application site reactions were reported in a higher percentageof females than males in both imiquimod groups but were rare for bothgenders in the placebo group. The incidence of SAEs and AEs leading tostudy discontinuation was low in all treatment groups regardless ofgender.

Within each gender subgroup, the percentage of subjects reporting AEs inthe 3.75% and 2.5% imiquimod treatment groups was similar.

Adverse Events by Age:

As in the overall population, application site reactions were the mostcommonly-reported treatment-emergent AEs and treatment-related AEs inboth age groups for all treatment groups.

In the active treatment groups, the incidence of treatment-emergent AEswas greater in older subjects (>35 years) than in younger (535 years)subjects; however, the proportions were similar in the placebo group.Treatment-emergent AEs were reported in 22.7%, 27.8%, and 22.2%,respectively, of younger subjects in the 3.75% imiquimod group, 2.5%imiquimod group, and placebo group compared with 36.5%, 31.7%, and24.0%, respectively, of the older subjects in the 3.75% imiquimod group,2.5% imiquimod group, and placebo group.

In the younger subgroup, the incidence of treatment-related AEs andapplication site reactions was similar between the 2 active treatmentgroups. In older subjects, the incidence of treatment-related AEs andapplication site reactions was slightly higher in the 3.75% imiquimodgroup than in the 2.5% imiquimod group. Few treatment-related AEs orapplication site reactions were reported in subjects in either age groupwho received placebo.

Adverse Events by Number of Anatomic Areas:

As in the overall population, the most commonly-reportedtreatment-emergent AEs and treatment-related AEs in both subgroups forall treatment groups were application site reactions.

In the 3.75% imiquimod group, higher percentages of subjects in themultiple-area subgroup than in the single-area subgroup reported any AE(30.3% and 24.0%, respectively), a treatment-related AE (22.2% and 8.3%,respectively), or an application site reaction (22.2% and 7.3%,respectively). There was little difference in AE incidence between thesubgroups in the 2.5% imiquimod and placebo treatment groups.

The proportion of subjects with a treatment-related AE or an applicationsite reaction in the multiple-area subgroup was higher in the 3.75%imiquimod group than in the 2.5% imiquimod group, whereas in thesingle-area subgroup, the proportion of subjects with atreatment-related AE or an application site reaction was higher in the2.5% imiquimod group compared with the 3.75% imiquimod group.

Adverse Events by Baseline Wart Count:

As in the overall population, application site reactions were the mostcommonly-reported treatment-emergent AEs in both subgroups for alltreatment groups. No trends in AE incidence with regard to baseline wartcount were observed.

In the subjects with 7 or fewer warts at Baseline, the incidence of AEswas 29.0%, 18.7%, and 22.2%, respectively, in the 3.75% imiquimod, 2.5%imiquimod, and placebo groups, whereas in subjects with more than 7warts at Baseline, the incidence of AEs was 25.0%, 40.2%, and 23.1%,respectively, in the 3.75% imiquimod, 2.5% imiquimod, and placebogroups.

In the subjects with 7 or fewer warts at Baseline, the incidence oftreatment-related AEs was 15.9%, 9.9%, and 2.2%, respectively, in the3.75% imiquimod, 2.5% imiquimod, and placebo groups, whereas in subjectswith more than 7 warts at Baseline, the incidence of treatment-relatedAEs was 14.8%, 20.7%, and 1.9%, respectively, in the 3.75% imiquimod,2.5% imiquimod, and placebo groups.

The incidence of treatment-related AEs or application site reactions wasgenerally similar in the active treatment groups and lower in theplacebo group.

Local Skin Reactions

Local skin reactions were assessed by the investigator at each visitincluding Baseline (pretreatment). At Baseline, 3.6%, 2.8%, and 3.1% ofsubjects in the 3.75% imiquimod, 2.5% imiquimod, and placebo groups,respectively, had at least one LSR reaction (LSR intensity score >0).The most intense post-Baseline LSRs (ie, those with the highestintensity rating) in the treatment areas that were assessed by theinvestigator over the course of the study are summarized in Table 127.The potential maximum sum of LSR scores was 18 (six types of LSRs eachwith a maximum potential score of 3).

TABLE 127 Frequency Distribution of Most Intense Post-baseline LocalSkin Reactions in the Treatment Area-Safety Population Number (%) ofSubjects Imiquimod Type of 3.75% 2.5% Placebo Reaction Intensity (N =195) (N = 178) (N = 97) Erythema N  180 (100)  162 (100)   92 (100) 0 =None   39 (21.7)   56 (34.6)   68 (73.9) 1 = Faint to mild redness   54(30.0)   48 (29.6)   20 (21.7) 2 = Moderate redness   70 (38.9)   42(25.9)   4 (4.3) 3 = Intense redness   17 (9.4)   16 (9.9) 0 >0 (anyreaction)  141 (78.3)  106 (65.4)   24 (26.1) Mean score (SD) 1.36(0.93) 1.11 (1.00) 0.30 (0.55) Edema N  180 (100)  162 (100)   92 (100)0 = None   98 (54.4)   95 (58.6)   85 (92.4) 1 = Mild visible/barely  54 (30.0)   42 (25.9)   6 (6.5) palpable swelling/ induration 2 =Easily palpable   23 (12.8)   22 (13.6)   1 (1.1) swelling/induration 3= Gross swelling/   5 (2.8)   3 (1.9) 0 induration >0 (any reaction)  82 (45.6)   67 (41.4)   7 (7.6) Mean score (SD) 0.64 (0.81) 0.59(0.79) 0.09 (0.32) Weeping/ N  180 (100)  162 (100)   92 (100) Exudate 0= None  110 (61.1)  111 (68.5)   90 (97.8) 1 = Minimal exudate   45(25.0)   36 (22.2)   1 (1.1) 2 = Moderate exudate   22 (12.2)   13 (8.0)  1 (1.1) 3 = Heavy exudate   3 (1.7)   2 (1.2) 0 >0 (any reaction)   70(38.9)   51 (31.5)   2 (2.2) Mean score (SD) 0.54 (0.77) 0.42 (0.69)0.03 (0.23) Flaking/ N  180 (100)  162 (100)   92 (100) Scaling/ 0 =None  122 (67.8)  121 (74.7)   82 (89.1) Dryness 1 = Milddryness/flaking   52 (28.9)   32 (19.8)   9 (9.8) 2 = Moderate dryness/  6 (3.3)   8 (4.9)   1 (1.1) flaking 3 = Severe dryness/ 0   1 (0.6) 0flaking >0 (any reaction)   58 (32.2)   41 (25.3)   10 (10.9) Mean score(SD) 0.36 (0.55) 0.31 (0.59) 0.12 (0.36) Scabbing/ N  180 (100)  162(100)   92 (100) Crusting 0 = None  135 (75.0)  131 (80.9)   89 (96.7) 1= Crusting   33 (18.3)   21 (13.0)   1 (1.1) 2 = Serous scab   10 (5.6)  8 (4.9)   2 (2.2) 3 = Eschar   2 (1.1)   2 (1.2) 0 >0 (any reaction)  45 (25.0)   31 (19.1)   3 (3.3) Mean score 0.33 (0.63) 0.27 (0.61)0.05 (0.31) Erosion/ N  180 (100)  162 (100)   92 (100) Ulceration 0 =None  110 (61.1)  108 (66.7)   89 (96.7) 2 = Erosion   49 (27.2)   39(24.1)   3 (3.3) 3 = Ulceration   21 (11.7)   15 (9.3) 0 >0 (anyreaction)   70 (38.9)   54 (33.3)   3 (3.3) Mean score (SD) 0.89 (1.16)0.76 (1.11) 0.07 (0.36) SD = Standard deviation. Note: For purposes ofanalysis, ‘Erosion’ is categorized as 2 = Moderate, and ‘Ulceration iscategorized as 3 = Severe. Denominator for the most intense reaction isthe number of subjects with at least one post-baseline assessment.

As displayed in Table 127, the incidence of each type of LSR was higherin the active treatment groups compared with placebo. For each LSR, thepercentage of subjects with any reaction and the mean intensity scorewere highest in the 3.75% imiquimod treatment group, somewhat lower inthe 2.5% imiquimod group, and lowest in the placebo group. The incidenceof severe LSRs was similar between the active treatment groups withineach. LSR category, and lower in the placebo group.

Erythema was the LSR reported with the greatest frequency and thegreatest mean intensity in all 3 treatment groups. Severe erythema wasreported in 9.4% and 9.9% of subjects in the 3.75% and 2.5% imiquimodgroups, respectively, and in no subjects in the placebo group. The meanintensity score was higher in the active treatment groups (1.36 and 1.11in the 3.75% and 2.5% imiquimod groups, respectively) compared withplacebo (0.30). Edema rated as severe was reported in 2.8% and 1.9% ofsubjects in the 3.75% and 2.5% imiquimod groups, respectively, and in nosubjects in the placebo group. The mean intensity scores were higher inthe active treatment groups (0.64 and 0.59 in the 3.75% and 2.5%imiquimod groups, respectively) compared with 0.09 in the placebo group.

For erosion/ulceration, severe reactions (ulceration) were reported in11.7% and 9.3% of subjects in the 3.75% and 2.5% imiquimod groups,respectively, and in no subjects in the placebo. The mean intensityscores were higher in the active treatment groups (0.89 and 0.76 in the3.75% and 2.5% imiquimod groups, respectively) compared with 0.07 in theplacebo group.

The majority of cases of weeping/exudate, flaking/scaling, andscabbing/crusting were mild in intensity. Few subjects in any treatmentgroup had a reaction considered to be severe.

A summary of subjects who had any local skin reaction is presented inTable 128.

TABLE 128 Summary of Subjects Who Had Any Local Skin Reaction During theStudy-Safety Population Number (%) of Subjects Imiquimod Most IntenseReaction 3.75% 2.5% Placebo (post-Baseline) (N = 195) (N = 178) (N = 97)N 180 162 92 0 = None   36 (20.0)   52 (32.1)   63 (68.5) 1 = Mild   48(26.7)   37 (22.8)   22 (23.9) 2 = Moderate   64 (35.6)   49 (30.2)   7(7.6) 3 = Severe   32 (17.8)   24 (14.8)  0 >0 (any reaction)  144(80.0)  110 (67.9)   29 (31.5) Mean score (SD)  1.5 (1.0)  1.3 (1.1) 0.4 (0.6) SD = Standard deviation. For purposes of analysis, ‘Erosion’is categorized as 2 = Moderate and ‘Ulceration’ is categorized as 3 =Severe. Denominator for the most intense reaction is the number ofsubjects with at least one post-baseline assessment.

As noted for the individual LSRs, the percentage of subjects reportingan LSR at each intensity category was higher in the active treatmentgroups compared with placebo, and was somewhat higher with 3.75%imiquimod than with 2.5% imiquimod. Severe reactions were reported by17.8% of subjects in the 3.75% imiquimod group and 14.8% of subjects inthe 2.5% imiquimod group compared with no subjects in the placebo group.The mean score for most intense LSR reaction was slightly higher in the3.75% imiquimod group (1.5) than in the 2.5% imiquimod group (1.3).

The mean LSR sum score is shown by study week in FIG. 34. Erythema wasthe major contributor to the LSR sum score in all treatment groups, asdetermined by visual inspection. In the imiquimod treatment groups, themean LSR sum score peaked at Week 2, decreased slightly during thetreatment period, and rapidly decreased when treatment was discontinued.Mean LSR scores in the placebo group were highest at Week 4 and Week 6,but were considerably lower than those seen with active treatment.

Rest Periods

Summaries of the rest periods for the safety population are presented inTable 129.

TABLE 129 Summary of Rest Periods-Safety Population IMIQUIMOD CREAM3.75% 2.5% PLACEBO (N = 195) (N = 178) (N = 97) Subjects requiring restperiod, n/N (%)^(a)   59 (30.3)   49 (27.5) 1 (1.0) P value vs Placebo <0.001 <0.001 NA P value vs 2.5% imiquimod cream    0.567 NA NA No. ofdosing days missed due to rest period^(b) N   59   49 1 Mean (SD)  7.9(6.2) 10.0 (7.0) 3.0 Median    7    8 3 P value vs Placebo    0.310   0.224 NA P value vs 2.5% cream    0.105 NA NA No. of dosing days riorto the beginning of the first rest period^(b) N   57   49 1 Mean (SD)17.8 (12.4) 19.3 (11.9) 15.0 Median   14   14 15 P value vs Placebo   0.631    0.945 NA P value vs 2.75% cream    0.455 NA NA No. = number;SD = standard deviation; NA = not applicable ^(a)P values are fromCochran-Mantel-Haenszel test, stratified by gender and analysis site,taking 2 treatment groups at a time. ^(b)P values are from the WilcoxonRank Sum test, taking 2 treatment groups at a time.

Significantly larger percentages of subjects in the active treatmentgroups compared with placebo took a rest period during the study(P<0.001). There was no significant difference between the activetreatments in the percentage of subjects who took a rest period (30.3%and 27.5% in the 3.75% and 2.5% imiquimod groups, respectively). Therewere no statistically significant differences between the treatmentgroups in the mean duration of rest periods or the mean number of dosingdays prior to the rest periods.

Analysis of Adverse Events

Application site reactions are commonly reported for topically appliedproducts. An additional analysis of these events is presented below.Application site reactions reported in this study are displayed in Table130 below:

TABLE 130 Number (%) of Subjects with Treatment-Emergent ApplicationSite Adverse Events-Safety Population Imiguimod Cream 3.75% 2.5% Placebo(N = 195) (N = 178) (N = 97) Subjects with any application 29 (14.9) 25(14.0) 2 (2.1) site reaction, n (%) Number of application 57 36 3 sitereactions Number (%) of subjects with any: Related Application Site 29(14.9) 24 (13.5) 2 (2.1) Reaction^(a), n (%) Serious Application Site  0 0 0 Reaction, n (%) Severe Application Site  3 (1.5)  6 (3.4) 0Reaction, n (%) Application Site Reaction  2 (1.0)  2 (1.1) 0 Leading toStudy Discontinuation, n (%) General disorders and 28 (14.4) 25 (14.0) 2(2.1) administration site conditions, n (%) Application site pain 11(5.6) 12 (6.7) 1 (1.0) Application site irritation 12 ( 6.2)  5 (2.8) 1(1.0) Application site pruritus  3 (1.5)  3 (1.7) 1 (1.0) Applicationsite reaction  3 (1.5)  3 (1.7) 0 Application site discharge  3 (1.5)  2(1.1) 0 Application site erythema  3 (1.5)  2 (1.1) 0 Application siteerosion  2 (1.0)  1 (0.6) 0 Application site oedema  2 (1.0)  1 (0.6) 0Application site bleeding  2 (1.0)  0 0 Application site excoriation  2(1.0)  0 0 Application site rash  2 (1.0)  0 0 Application site ulcer  0 2 (1.1) 0 Application site dermatitis  0  1 (0.6) 0 Application sitediscomfort  0  1 (0.6) 0 Infections and infestations, n (%)  1 (0.5)  00 Application site cellulitis  1 (0.5)  0 0 ^(a)Includes ‘Probablyrelated’ and ‘Related’ adverse events. Counts reflect numbers ofsubjects in each treatment group reporting 1 or more AEs that map to theMedDRA system organ class. A subject may be counted once only in eachrow of the table.

The incidence of application site adverse events and treatment-relatedapplication site events was similar in the 3.75% and 2.5% imiquimodtreatment study groups. Few subjects in the active treatment groups andno subjects in the placebo group reported severe application site eventsor application site events that led to study withdrawal. No seriousapplication site reactions were reported in any study group.

The most commonly reported application site reactions were applicationsite pain and application site irritation.

TABLE 131 Number (%) of Subjects with Serious Adverse Events-SafetyPopulation Imiquimod Cream 3.75% 2.5% Placebo (N = 195) (N = 178) (N =97) Subjects with any SAE, n (%) 2 (1.0) 2 (1.1) 0 Subjects with anytreatment-emergent SAE, n (%) 1 (0.5) 2 (1.1) 0 Subjects with anyrelated SAE, n (%) 0 0 0 Serious adverse events Iron deficiency anemia 01 (0.6) 0 Acute abdomen 1 (0.5) 0 0 Pelvic mass 1 (0.5) 0 0 Migraine 0 1(0.6) 0 Syncope 0 1 (0.6) 0 Cholecystolithiasis^(a) 1 (0.5) 0 0 Countsreflect numbers of subjects in each treatment group reporting one ormore adverse events that map to the MedDRA system organ class. A subjectwas counted only once in each row of the table. ^(a)One subject had anSAE that was not considered treatment-emergent.

Few SAEs were reported during the study. Treatment-emergent SAEsoccurred in 1 subject (0.5%) in the 3.75% imiquimod group, 2 subjects(1.1%) in the 2.5% imiquimod group, and no placebo subjects. Oneadditional subject in the 3.75% imiquimod group had an SAE(cholecystolithiasis) that occurred during the follow-up for recurrenceperiod and was not considered treatment-emergent. None of the SAEs wereconsidered related to study treatment and all resolved with no sequelae.

Other Significant Adverse Events

Treatment-emergent AEs that led to discontinuation from the study arepresented in Table 132 below:

TABLE 132 Number (%) of Subjects with Treatment-Emergent Adverse EventsLeading to Study Discontinuation-Safety Population Imiquimod Cream 3.75%2.5% Placebo (N = 195) (N = 178) (N = 97) Subjects with an AE leading to3 (1.5) 2 (1.1) 1 (1.0) study discontinuation, n (%) Subjects with atreatment- 2 (1.0) 2 (1.1) 0 related AE leading to studydiscontinuation, n (%) Adverse events leading to discontinuationApplication site erythema 1 (0.5) 0 0 Application site reaction 1 (0.5)1 (0.6) 0 Application site discharge 1 (0.5) 0 0 Application sitedermatitis 0 1 (0.6) 0 Pelvic mass 1 (0.5) 0 0 Acute abdomen 1 (0.5) 0 0Bronchitis 0 0 1 (1.0) Counts reflect numbers of subjects in eachtreatment group reporting one or more adverse events that map to theMedDRA system organ class. A subject was counted only once in each rowof the table. A treatment-emergent AE is an AE that began or worsened inseverity after the first application of the study drug and no more than30 days after the last application of the study drug. Treatment-relatedincludes Probably Related and Related.

The incidence of AEs that led to study discontinuation was low in alltreatment groups. Two subjects (1.0%) in the 3.75% imiquimod group and 2subjects (1.1%) in the 2.5% imiquimod group withdrew from the study forAEs that were considered related to study treatment; all of these wereapplication site reactions. Two subjects discontinued the study for AEconsidered not related to study treatment; a pelvic mass and an acuteabdomen in 1 subject in the 3.75% imiquimod group and bronchitis in oneplacebo subject. The AEs that led to study withdrawal resolved withoutsequelae, with the exception of 2 application site AEs, each in 1subject. As the EOS/early termination visit was the last contact withboth subjects, the events were recorded as “ongoing.”

Analysis and Discussion of Serious Adverse Events, and Other SignificantAdverse Events

No deaths occurred among the subjects in this study. The incidence ofSAEs was low in this study. No SAE was considered related to studytreatment and all resolved with no sequelae. Few subjects discontinuedthe study as a result of an AE. All of the treatment-related AEs leadingto study withdrawal were application site reactions. Only two AEs (bothapplication site reactions) were noted as ongoing at EOS.

Clinical Laboratory Evaluation

For most of the hematology, chemistry, and urinalysis variables, resultsin the majority of the subjects were normal at Screening and at EOS.Occasional shifts from normal at Screening to above or below the normalrange were observed; however, no dose-response relationship was evident.

For the clinical chemistry determinations, shifts from normal to highwere most frequently recorded for glucose (9/140 in the 3.75% imiquimodgroup, 10/125 in the 2.5% imiquimod group, and 10/70 in the placebogroup), AST (8/140 in the 3.75% imiquimod group, 10/125 in the 2.5%imiquimod group, and 1/69 in the placebo group), and ALT (9/140 in the3.75% imiquimod group, 11/125 in the 2.5% imiquimod group, and 4/70 inthe placebo group). Low cholesterol was noted in 9/141 subjects in the3.75% imiquimod group, 9/125 in the 2.5% imiquimod group, and 2/70 inthe placebo group).

In the hematology analyses, shifts from normal to high were mostfrequently recorded for white blood cell counts (4/138 in the 3.75%imiquimod group, 6/124 in the 2.5% imiquimod group, and 6/68 in theplacebo group). Shifts from normal to low were most frequently recordedfor red blood cell counts (7/138 in the 3.75% imiquimod group, 6/124 inthe 2.5% imiquimod group, and 2/68 in the placebo group).

The most commonly-reported shift observed in the study was a shift fromnormal to high in urine protein (34/134 subjects [25.4%] in the 3.75%imiquimod group, 22/120 subjects [18.3%] in the 2.5% imiquimod group,and 18/69 subjects [26.1%] in the placebo group). However, 34% ofsubjects (46/134) in the 3.75% imiquimod group, 38% of subjects (45/120)in the 2.5% imiquimod group, and 46% of subjects (32/69) in the placebogroup had high concentrations of urinary protein at Screening. Otherfindings from urinalysis included shifts from normal to high for bloodin the urine (10/134 subjects in the 3.75% imiquimod group, 7/120subjects in the 2.5% imiquimod group, and 2/69 subjects in the placebogroup).

Safety Conclusions

Mean exposure to study medication was approximately 43 packets, 46packets, and 52 packets of study medication in the 3.75% imiquimod, 2.5%imiquimod, and placebo groups, respectively. Mean treatment duration wassimilar among the study groups and ranged from 47.8 days in the 3.75%imiquimod group to 52.8 days in the placebo group.

Treatment-emergent AEs were reported in 27.2%, 29.2%, and 22.7% ofsubjects in the 3.75% imiquimod, 2.5% imiquimod, and placebo groups,respectively. Most AEs were mild or moderate in intensity. Applicationsite reactions were the most frequently reported AEs. Adverse events ofthe system organ classes “general disorders and administration siteconditions” and “infections and infestations” were the most frequentlyreported, and the incidence of these events was similar in the activetreatment groups. The incidence of severe LSRs was similar in the activetreatment groups.

The incidence of systemic symptoms (ie, flu-like symptoms, etc)previously noted with 5% imiquimod was low (≤1%) in this study.

Treatment-emergent SAEs were reported in 1 subject in the 3.75%imiquimod group, 2 subjects in the 2.5% imiquimod group, and noplacebo-treated subjects; none were considered treatment-related.

Treatment-emergent AEs that led to study discontinuation were reportedin 3 subjects, 2 subjects, and 1 subject in the 3.75% imiquimod, 2.5%imiquimod, and placebo groups, respectively. Four subjects (2 in each ofthe imiquimod groups) withdrew from the study for TEAEs consideredrelated or probably related to study treatment, and all were applicationsite reactions.

The incidence of TEAEs and severe AEs was higher in females than inmales across all treatment groups, and the incidence of application sitereactions was higher in females than in males in the active treatmentgroups. Serious AEs and AEs leading to study discontinuation were rarein all treatment groups regardless of gender.

Local skin reactions were reported in 80.0%, 67.9%, and 31.5% ofsubjects in the 3.75% imiquimod, 2.5% imiquimod, and placebo groups,respectively. The incidence and severity of LSRs was higher in theactive treatment groups than in the placebo group. Erythema was the LSRreported with the greatest frequency and the greatest mean intensity inall treatment groups. Local skin reactions were coincident with thetreatment period and rapidly decreased when treatment was concluded. Theincidence of severe intensity LSRs was similar in the active treatmentgroups.

Rest periods were taken by 59 subjects (30.3%), 49 subjects (27.5%), and1 subject (1.0%) in the 3.75% imiquimod, 2.5% imiquimod, and placebogroups, respectively. The frequency, duration, and number of dosing daysprior to the rest period were similar in the active treatment groups andlower in the placebo group.

There was no evidence of clinically meaningful trends in vital signmeasurements or clinical laboratory measurements. Two subjects, both inthe 2.5% imiquimod group, had abnormal laboratory values that werereported as AEs; only 1 (a moderate increase in blood lactatedehydrogenase) was considered probably related to study treatment.

Discussion

In this double-blind, placebo controlled clinical study, 470 subjectswith EGW diagnosed by clinical examination were randomized to receivetreatment with 3.75% imiquimod cream, 2.5% imiquimod cream, or amatching placebo cream. During the evaluation period, subjects appliedstudy medication once daily to the identified treatment area(s) for amaximum of 8 weeks. If the subject did not achieve complete wartclearance by the Week 8 visit (end of treatment [EM]), the subject wasmonitored for an additional maximum 8 weeks of no treatment. Subjectsdetermined to have achieved complete clearance of all warts at any timeuntil Week 16 (end of study [EOS]) completed procedures for theend-of-study visit and were eligible to immediately enter the follow-upperiod for determination of wart recurrence. During the follow-upperiod, subjects were monitored every 4 weeks for up to 12 weeks oruntil the recurrence of warts. The 3.75% imiquimod cream demonstratedefficacy and tolerability as compared with placebo for treatment of EGW.Efficacy variables for the 2.5% imiquimod treatment group were superiorcompared with placebo, but the differences versus placebo were notconsistently statistically significant. Overall, 68.7% of subjectscompleted the evaluation period, and the discontinuation rates weresimilar in all treatment groups. Compliance with the daily treatmentregimen ranged from 84.3% in the 3.75% imiquimod group to 86.8% in theplacebo group.

Imiquimod has been demonstrated to be a safe and effective treatment forEGW. The dosing regimen for the currently approved product, 5% imiquimodcream, is 3 times per week for up to 16 weeks. Clinical experience hasshown compliance with this regimen is challenging, as the treatmentduration is long and the application schedule is non-intuitive. Thecurrent study was designed to evaluate imiquimod cream in lowerconcentrations to permit a more intuitive daily-dosing regimen and ashortened treatment regimen (up to 8 weeks) that provides acceptableefficacy and tolerability.

Efficacy

Efficacy was demonstrated for the primary efficacy measure as well asfor the secondary and tertiary efficacy measures for the 3.75% imiquimodcream. Results for all efficacy measures for which statistical testingwas performed were highly statistically significant in the 3.75%imiquimod treatment group as compared with placebo in both the ITT andPP populations. For the 2.5% imiquimod cream, the efficacy measurementswere superior to those with placebo, but the differences were notconsistently statistically significant.

Measures of wart reduction showed pronounced treatment effects for thehigher concentration product (complete clearance rates of 27.2%, 19.1%and 10.3%; ≥75% clearance rates of 37.9%, 27.0%, and 13.4%; mean percentchange in wart count of −45.8%, −26.6%, and −9.4%; and at least 50%reduction in wart count in 50.8%, 34.3%, and 19.6% of subjects in the3.75% imiquimod, 2.5% imiquimod, and placebo groups, respectively, inthe ITT population).

It should be noted that the primary efficacy variable used in this study(complete clearance of all warts, both Baseline and newly emerged, inall assessed anatomic areas) was very conservative. Warts were countedin all assessed anatomic areas without distinction as to those wartsidentified at Baseline or those newly identified. In this study,subjects applied study medication to individual warts in variousanatomic areas identified at Baseline. Some subjects developed new wartsduring the study, and these new warts may have appeared in anatomicareas involved at Baseline as well as in newly involved anatomic areas.New warts were treated with study medication when they appeared, butreceived less than a full course of treatment, because treatment was notextended beyond 8 weeks from randomization/Day 1 visit. Subjects who didnot completely clear all warts by the Week 8/EOT visit were followed fora maximum 8 week no treatment period. As with evaluations during thedaily treatment phase, subjects were evaluated for the presence of EGWin all anatomic areas, and no distinction was made between baseline andnewly evident warts. As efficacy measures were based on completeclearance of all warts, not just warts presented at Baseline,development of new warts would potentially lower the complete andpartial clearance rates.

Subgroup analyses were performed for the primary efficacy variable. Ingeneral, the complete clearance rates increased in a dose-dependentmanner regardless of subgroup. The most striking subgroup effect wasobserved in the analysis by gender; the complete clearance rates wereconsistently higher in females than in males in all treatment groups.The higher absolute clearance rates in females than in males have beenseen previously with 5% imiquimod cream as well as with other topicaltreatments and may be due in part to the distribution of warts onfemales (eg, less keratinized skin). In addition to gender subgroup, thecomplete clearance rates tended to be higher in subjects with ≤7 wartsat Baseline, in subjects whose EGW was first diagnosed less than 1 year,in subjects who took a rest period, and in subjects with baseline wartsin the anatomic areas with less keratinized skin such as the perinealarea, the perineal area, the foreskin, or the vulva. Of note, baselinedemographics for the population as a whole suggest that EGWs in thisstudy cohort were of relatively longstanding duration (mean/median yearssince diagnosis of 4.3/1.4 years).

Safety

Daily application of 3.75% or 2.5% imiquimod cream was generally welltolerated in this study. Few subjects discontinued the study due toadverse events. Very few serious adverse events were reported, and nonewere considered treatment related. The proportion of subjects withtreatment-related AEs was higher in the active treatment groups (15.4%and 15.2% in the 3.75% and 2.5% imiquimod, respectively) than withplacebo (2.1%), but there was no difference in the incidence ratesbetween imiquimod groups. Most AEs were mild or moderate ill intensity,and resolved without sequelae.

The majority of AEs considered treatment related occurred in the systemorgan class General Disorders and Administrative Site Conditions, andare not unanticipated with imiquimod. For the most part, theserepresented various application site reaction symptoms such as pain,irritation, pruritus, etc. The proportion of subjects with anyapplication site reaction was similar in the active treatment groups.

Anticipated reactions in the application area were also capturedseparately as local skin reactions (LSRs). The frequency and intensityof LSRs were higher in the active treatments compared with placebo.Erythema was the LSR reported with the greatest frequency and thegreatest mean intensity in all treatment groups. The incidence of severeintensity LSRs was similar in the active treatment groups. Local skinreactions were coincident with the treatment period and rapidlydecreased when treatment was concluded.

There was no evidence of clinically meaningful trends in vital signmeasurements or clinical laboratory measurements.

Conclusion

The 3.75% cream formulation of imiquimod demonstrated substantialefficacy for the treatment of EGW. All efficacy measures for whichstatistical testing was performed were significantly superior in the3.75% imiquimod treatment group compared with placebo in both the ITTand PP populations. Consistently greater efficacy was observed with the3.75% imiquimod product compared with 2.5% imiquimod, and the safetyprofiles were similar. Treatment with either imiquimod formulationresulted in greater increases in local skin reactions compared with theplacebo cream: erythema was the LSR reported with the greatest frequencyand the greatest mean intensity in all treatment groups. For both activecreams, the number and severity of local skin reactions decreasedrapidly after the completion of treatment. The most frequently reportedadverse events were application site reactions observed in the activetreatment groups; however, few subjects discontinued the study as aresult of adverse events, indicating that these events were manageableand generally well tolerated.

Example 25

The Combined Two Phase 3, Randomized, Double-Blind, Placebo-Controlled,Multi-Center, Efficacy and Safety Studies of 3.75% Imiquimod Creams inthe Treatment of External Genital Warts, as Reported in Example 24 andin the Draft U.S. Label and the Canadian Product Monograph IncorporatedHerein by Reference in their Entireties and Filed ContemporaneouslyHerewith

In two double-blind, randomized, placebo-controlled clinical studies,601 subjects with EGW were treated with 3.75% imiquimod cream, or amatching placebo cream-studies enrolled subjects aged from 15 to 81years. The baseline wart area ranged from 6 to 5579 mm2 and the baselinewart count ranged from 2 to 48 warts. Most subjects had two or moretreated anatomic areas at Baseline. Anatomic areas included: inguinal,perineal, and perianal areas (both genders); the glans penis, penisshaft, scrotum, and foreskin (in men); and the vulva (in women). Up toone packet of study cream was applied once daily to each wart identifiedat Baseline and any new wart that appeared during the treatment period.The study cream was applied to all warts prior to normal sleeping hoursand left on for approximately 8 hours. Subjects continued applying thestudy cream for up to 8 weeks or until they achieved complete clearanceof all (baseline and new) warts in all anatomic areas. Subjects notachieving complete wart clearance by the Week 8 visit (end of treatment.EOT), were evaluated for up to 8 weeks or until they achieved completeclearance during an additional 8, week no-treatment period. Subjects whoachieved complete clearance of all warts at any time until the Week 16visit entered a 12 week follow-up for recurrence period.

Efficacy was assessed by wart counts (those present at Baseline and newwarts appearing during the study) at EOS (i.e., up to 16 weeks fromBaseline). Complete clearance required clearance of all warts in allanatomic areas. Partial clearance rate was defined as the proportion ofsubjects with at least a 75% reduction in the number of baseline wartsat EOS. Percent reductions were measured relative to the numbers ofwarts at Baseline. Complete and partial clearance rates, and percentreductions in wart counts from baseline are shown in the Table 133 below(by overall rate and by gender).

TABLE 133 Efficacy End Points TRADENAME ™ Placebo Cream, 3.75% CreamComplete Clearance Rate Overall 28.3% (113/399) 9.4% (19/202) Females36.6% (79/216) 14.2% (15/106) Males 18.6% (34/1 83) 4.2% (4/96) PartialClearance Rate Overall 38.3% (153/399) 11.9% (24/202) Females 47.7%(103/216) 17.0% (18/106) Males 27.3% (50/183) 6.3% (6/96) PercentReduction of EGW Overall 50.0% 0.0 Females 70.7% 0.0 Males 23.3% 0.0

The numbers of subjects who remained clear of EGW at the end of 12 weekfollow-up for recurrence period are shown in Table 134 below:

TABLE 134 Sustained Complete Clearance TRADENAME ™ Placebo Cream, 3.75%Cream Cleared and entered Follow-up 102 13 Remained Clear 71 12

Systemic absorption of imiquimod (up to 9.4 mg [one packet]) across theaffected skin of 18 subjects with EGW was observed with once dailydosing for 3 weeks. The mean peak serum drug concentration at Day 21 wasabout 0.488 ng/mL.

Acute dermal toxicity studies in rabbits with unformulated imiquimodunder occlusion did not reveal any toxic effects at very high doselevels—5000 mg/kg. When administered orally, intraperitoneally,subcutaneously or intravenously, single dose studies revealed thatimiquimod produced central nervous system (CNS) stimulation andconvulsions at lethal doses. However, signs of CNS toxicity did notoccur when animals were given lower repeat doses (100 mg/kg or lower) asshown in Table 135.

TABLE 135 Species Route LD₅₀ (mg/kg) Mouse Oral  403 Intraperitoneal 879 Rat Oral 1665 Intraperitoneal  763 Subcutaneous  ≈20   RabbitDermal >5000   Monkey Oral  >200   intravenous infusion   ≈8  intravenous bolus   >6  

As indicated above, in two double-blind, placebo-controlled studies forgenital warts, 602 subjects applied up to one packet of a cream of thepresent invention or placebo daily for up to 8 weeks. The mostfrequently reported adverse reactions were local skin and applicationsite reactions.

Overall, fewer than 1% (3/400) of the subjects treated with a cream ofthe present invention discontinued due to local skin application sitereactions. The incidence and severity of local skin reaction duringcontrolled clinical studies are shown in Table 136.

TABLE 136 Local Skin Reactions in the Treatment Area Assessed by theInvestigator TRADENAME Cream Placebo Females Males Females Males n = 217n = 183 n = 106 n = 96 All All All All Grades* Severe Grades* SevereGrades* Severe Grades* Severe Erythema 74% 10% 78% 10% 23% 0% 37% 1%Edema 41%  2% 48%  2%  8% 0%  9% 0% (induration Weeping! 35%  1% 39%  3% 5% 0%  0% 0% Exudate Flaking! 26%  0% 39%  0% 11% 0% 11% 0% Scaling!nrwile.cc Scabbing! 18% <1% 34%  1%  6% 0%  2% 0% Crusting Erosion! 36%13% 42% 10%  7% 1%  2% 0% Ulceration *Mild, Moderate, or Severe

Local skin reactions were recorded as adverse events if they extendedbeyond the treatment area, if they required any medical intervention, orthey resulted in patient discontinuation from the study.

Selected treatment related adverse reactions are listed below.

TABLE 137 Treatment Related Adverse Reactions Occurring in >1% of aCream of Present Invention Treated Subjects and at a Greater Frequencythan with Placebo in either Gender Females Males TRADE- TRADE- NAME NAMECream Placebo Cream Placebo Preferred Term n = 217 n = 106 n = 183 n =96 Application site pain 7.8% 0% 5.5% 1.0%   Application site irritation5.5% 0.9%   6.0% 1.0%   Application site pruritus 3.2% 1.9%   1.6% 0%Application site bleeding 1.4% 0.9%   1.5% 0% Application site discharge1.4% 0% 0.5% 0% Application site erythema 1.4% 0%   0% 0% Applicationsite reaction 0.9% 0% 1.1% 0% Application site rash 0.9% 0% 1.1% 0%Scrotal pain   0% 0% 1.6% 0% Application site   0% 0% 1.1% 0%excoriation Secretion discharge   0% 0% 1.1% 0% Scrotal erythema   0% 0%1.1% 0% Scrotal ulcer   0% 0% 1.1% 0% Scrotal edema   0% 0% 1.1% 0%Pruritus genital   0% 0% 1.1% 0% Application site cellulitis   0% 0%1.1% 0%

Systemic adverse reactions considered treatment related in clinicaltrials involving a cream of the present invention included pain, pyrexia(fever), influenza, and myalgia.

Adverse reactions seen in clinical trials for external genital wartsinvolving 5% imiquimod cream included: tinea cruris, application sitesoreness, hypopigmentation, sensitivity, stinging and tenderness.

Other systemic adverse reactions considered treatment related inclinical trials for external genital warts involving 5% imiquimod creamincluded: headache, influenza-like symptoms, fatigue, malaise, nausea,and diarrhea.

Example 26

An Open Label, Single Center, Non-Randomized Pharmacokinetic Study toEvaluate Safety of and Systemic Exposure to Multiple Applications ofImiquimod Cream in Subjects with External Genital Warts

Objectives

To quantify the pharmacokinetics of imiquimod and its metabolites during3 weeks of daily applications of 3.75% imiquimod cream in subjects withexternal genital warts (EGW) under maximal use conditions. Secondaryobjectives include subject tolerability and safety assessments.

Methodology

In this open-label, single-center, non-randomized, pharmacokinetic (PK)study, approximately 18 adult subjects (a target of at least 5 subjectsof each gender) with at least 8 warts in the genital/perianal area or atotal wart area of ≥100 mm² applied once daily applications of up to 1packet of 3.75% imiquimod cream for 3 continuous weeks (21 days). Thestudy was conducted under the maximal use conditions (dose, diseaseseverity, and wart area) anticipated in Phase III studies.

Subjects stayed at the study center overnight during the treatmentinitiation visit (Day 1, first evening application) and theend-of-treatment visit (Day 21, last evening application). On Days 1 and21, serum PK samples were collected pre-application and at planned timepoints for 24 hour post application; samples were also collected at 48and 72 hours after application on Day 21. In addition, serum PK sampleswere collected in the evening prior to application on Days 7 and 14 todetermine trough concentrations for steady-state analysis.

Adverse events (AEs), local skin reactions (LSRs), number of warts, wartarea measurements, concomitant medication use, study medicationaccountability, and subject compliance were reviewed at each visit.Routine clinical laboratory assessments (serum chemistry, hematology,and urinalysis) were performed at screening and 72 hours after the lastapplication on Day 21.

This study was performed primarily to determine the pharmacokinetics of3.75% imiquimod cream during 3 weeks of once daily application insubjects with EGW; consequently, an open-label, non-randomized studydesign was chosen. Since the pharmacokinetics of imiquimod have beenevaluated in several studies, a control group was consideredunnecessary, and since mean urinary recoveries of imiquimod and itsmetabolites were low in a previous study of EGW subjects (Study1253-IMIQ₉), urinary pharmacokinetic analyses imiquimod and itsmetabolites were not performed in this study. Local skin reactions(LSRs) were assessed independently of adverse events (AEs). Standardsafety assessments used in clinical research were included for theevaluation of safety and tolerability.

The 3-week treatment duration was selected to confirm that steady-stateconditions would exist with a relatively constantly applied dose/wartarea. Steady-state conditions for thrice weekly dosing of 5% imiquimodwere previously attained within 2 weeks of dosing in subjects with EGWs.A pharmacokinetic study was conducted in subjects with EGWs (Study1253-IMIQ), during which 12 subjects received 5% imiquimod creamadministered 3-times weekly for 16 weeks. While the trough levels inthis study were insufficient to determine whether steady-stateconditions were achieved (virtually all results were below the lowerlimit of quantification, LLOQ), the mean C_(max) values at Weeks 4 and16 were within the range of those observed after the first dose, and themeasured half-life values ranged from 3.4 to 33.4 hours. As a result,steady-state conditions would exist after 7 days of treatment at thelongest measured half-life value (33.4 hours). Following 21 days of oncedaily administration, steady-state conditions would be achieved if thehalf-life value was ≤100 hours (3 times the highest value observed inStudy 1253-LMIQ). Since the measured elimination half-life valuespreviously observed in EGWs subjects were consistent with shorter timesto steady state (i.e., 1 to 2 weeks), subjects were expected to attainsteady-state conditions within the 3 weeks of this study.

Inclusion Criteria

Subjects could participate in the study if they

-   1. Were willing and able to give informed consent.-   2. Were at least 18 years of age.-   3. Were willing and able to participate in the study with two    overnight stays and frequent visits to the study center and to    comply with all study requirements.-   4. Had a negative pregnancy test result prior to the first    application of test medication (for women of childbearing potential)    and agreed to use an approved method of birth control while enrolled    in the study.-   5. Had a diagnosis of external genital/perianal warts with at least    8 warts or a total wart area of at least 100 mm2 in any of the    following anatomic locations:-   Both Sexes: In the inguinal, perineal, and perianal areas;-   Men: Over the glans penis, penis shaft, scrotum, and foreskin,    including the base of the penis; and-   Women: On the vulva, including the mons.-   6. Were in good general health as confirmed by a medical history,    physical examination, and laboratory tests at the screening visit.    Exclusion Criteria

Subjects who met any of the following criteria were excluded from thestudy if they:

-   1. Were women of childbearing potential who were pregnant,    lactating, or planning to become pregnant during the course of the    study-   2. Had any topical and/or destructive treatments for EGW within 4    weeks prior to first treatment-   3. Had received any of the following treatments within 4 weeks prior    to the first treatment:

a. Imiquimod

b. Interferon/interferon inducer

c. Cytotoxic drugs

d. Immunomodulators or immunosuppressive therapies

e. Oral antiviral drugs (with the exception of oral acyclovir andacyclovir-related drugs for suppressive or acute therapy of herpes oroseltamivir for prophylaxis or acute therapy of influenza)

f. Topical antiviral drugs (including topical acyclovir andacyclovir-related drugs) in the treatment areas

g. Podophyllotoxin/podofilox in the treatment areas

h. Oral and parenteral corticosteroids (inhaled/intranasal steroids werepermitted)

i. Topical steroids if greater than 2 g/day

j. Any other topical prescription therapy for any conditions in thetreatment areas k. Dermatologic/cosmetic procedures or surgeries in thetreatment areas

-   4. Had any evidence (physical or laboratory) of clinically    significant or unstable disease and/or any condition (e.g., renal    disease) that might interfere with the pharmacokinetic response to    the study treatment or alter the natural history of EGW-   5. Were currently participating in another clinical study or had    completed another clinical study with an investigational drug or    device within the past 30 days-   6. Had known or active chemical dependency or alcoholism as assessed    by the investigator-   7. Had known allergies to study drug or any excipient in the study    cream-   8. Were currently immunosuppressed or had a history of    immunosuppression-   9. Had a planned surgery that would cause an interruption of study    treatment-   10. Had sexual partners currently being treated with an approved or    investigational treatment for EGW-   11. Had any current or recurrent malignancies in the genital or wart    area-   12. Had any untreated or unstable genital infections (other than    genital warts)-   13. Had any of the following conditions:    -   Known human immunodeficiency virus (HIV) infection    -   An outbreak of herpes genitalis in the wart areas within 4 weeks        prior to Enrollment    -   Internal (rectal, urethral, vaginal/cervical) warts requiring or        undergoing treatment    -   A dermatological disease (e.g., psoriasis) or skin condition in        the wart areas that might cause difficulty with examination-   14. Females with clinically significant abnormalities on pelvic    examination or laboratory results showing high-grade pathology    (e.g., high-grade squamous intraepithelial lesion, moderate or    severe dysplasia, squamous cell carcinoma).    Removal of Subjects from Therapy or Assessment

Subjects could choose to withdraw from the study or be withdrawn by theinvestigator at any time without prejudice to their future medical care.Any subject who did not comply with the inclusion/exclusion criteriacould be withdrawn from further participation in the study.

Subjects were also discontinued from the study for the followingreasons:

-   -   The investigator determined that the subject experienced local        skin reactions (LSRs) of severe enough intensity or duration to        warrant discontinuation. If a subject discontinued due to an        LSR, the LSR was recorded as an adverse event (AE), and the        subject was followed until the AE resolved to the investigator's        satisfaction.    -   The subject took any prohibited medications or underwent any        prohibited treatments or procedures as described below.    -   The subject developed a dermatological condition within the wart        area unrelated to study cream that interfered with treatment        compliance.    -   The subject developed a malignancy within the wart area that        required intervention.    -   The subject became pregnant during the study.

Subjects who discontinued from the study were to complete theappropriate end-of-study procedures.

Prohibited medications/treatments or procedures:

a. Imiquimod 5% cream (Aldara®)

b. Interferon/interferon inducer

c. Cytotoxic drugs

d. Immunomodulators or immunosuppressive therapies

e. Oral or parenteral corticosteroids (inhaled/intranasal steroids arepermitted)

f. Oral antiviral drugs (with the exception of oral acyclovir andacyclovir-related drugs for suppressive or acute therapy of herpes oroseltamivir for prophylaxis or acute therapy of influenza)

g. Topical antiviral drugs (including topical acyclovir andacyclovir-related drugs) in the treatment areas

h. Podophyllotoxin/podofilox in the treatment areas

i. Any topical prescription medications in the application areas

j. Dermatologic/cosmetic procedures or surgeries in the applicationareas

A total of 18 subjects, 13 male subjects and 5 female subjects, wereenrolled (18 planned) who met the inclusion and exclusion criteria andwere able to participate within the time frame of this study. Allsubjects completed the study.

Criteria and Methods for Evaluation:

Efficacy was not evaluated in this study.

Primary Assessments:

The pharmacokinetics of imiquimod and its metabolites during 3 weeks ofdaily application with 3.75% imiquimod cream under the maximal useconditions (up to 1 packet of the cream applied to least 8genital/perianal warts or in an area of at least 100 mm²) werequantified.

During the 3-week treatment period, blood samples for determination ofthe concentrations of imiquimod (R-837) and two metabolites combined(S-26704 and S-27700) were collected at 9 time points on Day 1 (firstapplication) within approximately 30 minutes of pre-application (0 hour)and 1, 2, 4, 6, 9, 12, 16, and 24 hours after application of study creamand on Day 21 (last application) at pre-application and 1, 2, 4, 6, 9,12, 16, and 24 hours after application of study cream, Pharmacokinetic(PK) blood samples were also collected 48 hours after the lastapplication on Day 21, and End-of-Study (EOS) PK blood samples werecollected 72 hours after the final application. In addition, singleblood draws for PK analysis of trough concentrations to determine steadystate were obtained on Day 7 and Day 14 (in the evening prior toapplication). Blood samples could be obtained within ±5 minutes of thetarget sampling time.

Urine samples for PK analysis were not obtained during this study.

Serum PK samples were analyzed for concentrations of imiquimod (R-837)and two major metabolites (S-267046-27700) using validated analyticalmethods.

Secondary Assessments:

Adverse events and local skin reactions were evaluated during the study.

Severity, relationship to study medication and timing of adverse eventswere recorded.

Routine clinical laboratory assessments (serum chemistry, hematology andurinalysis) will be performed at Screening, Day 1, and the end of studyvisits.

Pharmacokinetic and Statistical Methods:

The concentration of imiquimod and its 2 metabolites combined (S-26704and S-27700) in serum over time will be used to calculatepharmacokinetic parameter estimates, when. sufficient data are present

Pharmacokinetic variables will be calculated from the serumconcentration data using standard, non-compartmental methods.

Pharmacokinetic Abbreviations and Definitions of Terms AUC_(0-inf) Areaunder the serum concentration versus time curve, from 0 to infinity;AUC_(0-inf) calculated as Day 1 as AUC(_(0-inf)) = AUC(_(0-inf)) +Ct/λ_(z) (where AUC_(0-t) = AUC from time zero to the time of the lastnon-zero concentration, C_(t) = the fitted last non-zero concentration,and λ_(z) = the elimination rate constant) AUC_(0-t) Area under theserum concentration versus time curve, from 0 to the time of the lastnon-zero concentration on Day 1; calculated using the linear trapezoidrule AUC₀₋₂₄ Area under the serum concentration versus time curve, from0 to 24 hours, calculated using the linear trapezoid rule orextrapolated to 24 hours in cases where reportable values were notobtainable up to that time point C_(max) Maximum serum concentration;the highest serum concentration observed during the dosing or samplinginterval C_(min) Minimum measurable serum concentration; serumconcentration observed immediately prior to dosing on Days 7, 14, 21,and 22 (24 hours post-dose) λ_(zEFF) Effective elimination rateconstant, calculated as -ln(1-1/R_(AUC))/tau λ_(z) Apparent eliminationrate constant; calculated using linear regression on the terminalportion of the in-concentration versus time profile R_(AUC) Accumulationratio; calculated as the AUC₀₋₂₄ value during multiple- applicationadministration divided by the AUC₀₋₂₄ value following the firstapplication (ie., Day 21/Day 1); accumulation ratios calculated for themetabolite only if sufficient non-zero time points were available toreasonably estimate AUC₀₋₂₄ R_(Cmax) Accumulation ratio; calculated asthe C_(max) value during multiple-application administration divided bythe C_(max). value following the first application (i.e., Day 21/Day 1)T_(1/2) The apparent elimination half-life, calculated as 0.693/λ_(z)T_(1/2 EFF) Effective half-life for accumulation; calculated as0.693/λ_(z EFF) T_(max) Time that C_(max) was observedResultsPharmacokinetics AnalysisSerum Concentrations

Mean serum concentrations of imiquimod and two of its metabolitescombined are shown using the linear and semi-log scales on Day 1 in FIG.35 and Day 21 in FIG. 36 below.

As shown in FIG. 35, the mean serum concentration of imiquimod (R-837)on Day 1 increased steadily until reaching a peak concentration ofapproximately 0.20 ng/mL at approximately 12 hours after the firstapplication of imiquimod 3.75% cream. By 24 hours after application, themean serum concentration of imiquimod had decreased to approximatelyhalf the peak concentration. Subject 001-411 had no concentrations aboveBLQ on Day 1; consequently, no pharmacokinetic parameters could becalculated for this subject on Day 1. Subject 001-408 had an imiquimodconcentration above BLQ (0.058 ng/mL) only at 12 hours on Day 1,limiting the pharmacokinetics that could be calculated. Serumconcentrations of the two imiquimod metabolites (S-26704 and S-27700combined) were undetectable on Day 1 except for Subject 001-418 who hada concentration of 0.056 ng/mL at 12 hours after application.

As shown in FIG. 36, mean serum concentrations of imiquimod on Day 21ranged from approximately 0.16 to 0.37 ng/mL over the 24-hour periodafter study drug application. Serum concentrations of two imiquimodmetabolites (S-26704 and S-27700 combined) were reported for only 4subjects on Day 21; the few concentrations that were reported tended tobe low (0.050 ng/mL to 0.133 ng/mL).

Pharmacokinetic Results

TABLE 137 Summary of Serum Pharmacokinetics for Imiquimod (R-837) on Day1 and Day 21 Mean (SD) Parameter N Day 1^(a) N Day 21^(b) C_(max) (n/mL)18 0.259 (0.223) 15 0.488 (0.368) C_(max) (n/mL) — NA 15 0.158 (0.121)T_(max) (hr)^(c) 17 12.00 (4.00-16.00) 15 12.00 (1.00-16.00) AUC₀₋₂₄ 153.748 (2.541) 15 6.795 (3.591) (ng · hr/mL) AUC_(0-t) 18 3.123 (2.665) —NA (ng · hr/mL) AUC_(0-inf) 12 5.352 (2.636) — NA (ng · hr/mL) λ_(z)(1/hr) 12 0.0756 (0.0416) 14 0.0370 (0.0222) T_(1/2) (hr) 12 12.450(8.249) 14 24.135 (12.402) R_(Cmax) — NA 14 2.260 (1.579) R _(AUC) — NA12 2.169 (1.752) λ_(z EFF) (hr⁻¹) — NA 10 0.0380 (0.0261) T_(1/2 EFF)(h⁻¹) — NA 10 31.328 (30.308) NA = Not applicable ^(a)Day 1 resultsinclude all PK population subjects. ^(b)Day 21 PK results include all PKpopulation subjects except Subject 001-404 (missed applications on Days8 and 18), Subject 001-407 (missed an application on Day 20), andSubject 001-416 (missed an application on Day 17). ^(c)Median(minimum-maximum)

TABLE 138 Summary Of Individual Serum Pharmacokinetic Parameters At Day21 For Imiquimod-Without Subjects 404, 407 And 416 Pk PopulationTREATMENT: 3.75 IMIQUIMOD CREAM QD ANALYTE: Serum R-837 SUBJECT/ CmaxTmax AUC(0-24) Lz Lzeff T ½ T½, eff STATISTICS (ng/mL) (hr.) (hr*ng/mL)RAUC RCmax (1/hr) (hr⁻¹) (hr) (hr) 001-401 0.140 12.000 2.201 1.1480.933 0.0516 0.0855 13.436 8.111 001-402 0.492 12.000 8.096 7.209 5.4070.0062 111.398 001-403 0.202 12.000 3.244 1.958 1.656 0.0293 0.029823.686 23.273 001-405 0.215 12.000 3.949 0.641 0.495 0.0128 53.990001-406 0.444 9.000 4.682 2.235 3.171 0.1022 0.0247 6.784 28.044 001-4080.281 4.000 3.723 4.845 0.0454 15.275 001-409 0.518 12.000 8.606 1.8441.609 0.0252 0.0326 27.514 21.294 001-410 0.659 9.000 10.296 4.3930.0219 31.695 001-411 0.359 9.000 6.732 0.0262 26.470 001-412 0.65112.000 11.536 3.178 1.876 0.0374 0.0157 18.51 44.024 001-413 0.10716.000 1.924 0.817 0.498 0.0163 42.622 001-414 0.446 4.000 6.232 1.8201.735 0.0408 0.0332 16.971 20.867 001-415 0.485 9.000 6.599 1.337 1.3940.0506 0.0574 13.712 12.077 001-417 0.692 12.000 10.379 2.639 2.0290.0317 0.0199 21.887 34.919 001-418 1.632 1.000 13.735 1.199 1.5970.0274 0.0748 25.337 9.270 N 15 15 15 12 14 14 10 14 10 MEAN 0.488 9.6676.795 2.169 2.260 0.0370 0.0380 24.135 31.328 SD 0.368 3.958 3.591 1.7521.579 0.0222 0.0261 12.402 30.308 CV % 75.318 40.946 52.843 80.77469.857 59.9435 68.6301 51.384 96.746 GEOMETRIC 0.392 8.291 5.834 1.7551.783 0.0324 0.0299 21.386 123.196 MEAN MIN 0.107 1.000 1.924 0.6410.495 0.0128 0.0062 6.784 8.111 MEDIAN 0.446 12.000 6.599 1.832 1.6960.0305 0.0312 22.786 22.284 MAX 1.632 16.000 13.735 7.209 5.407 0.10220.0855 53.99 111.398 During the last week, 3 subjects missedapplications (404 on Day 18, 407 on Day 20, and 416 on Day 17) and areexcluded from Day 21 results to provide data with subjects who appliedall applications.

TABLE 139 Summary of Individual Serum Pharmacolinetic Parameters- Cmin(Ng/Ml) by Day for Imiquimod, PK Population TREATMENT: IMIQUIMOD 3.75%CREAM QD ANALYTE: Serum R-837 (imiquimod) Subject ID/ Statistics Day 7Day 14 Day 21 Day 22 001-401 0.059 0.052 0.025 0.073 001-402 0.097 0.2770.263 0.240 001-403 0.142 0.315 0.075 0.099 001-404 0.194 0.199 001-4050.480 0.467 0.088 0.181 001-406 0.115 0.025 0.025 0.090 001-407 0.2140.276 001-408 0.073 0.125 0.137 0.099 001-409 0.237 0.376 0.221 0.272001-410 0.194 0.247 0.467 0.348 001-411 0.142 0.076 0.081 0.287 001-4120.287 0.025 0.269 0.370 001-413 0.025 0.025 0.025 0.077 001-414 0.2070.159 0.102 0.086 001-415 0.244 0.054 0.150 0.123 001-416 0.025 0.224001-417 0.126 0.196 0.192 0.228 001-418 0.111 0.165 0.246 0.145 N 18 1815 15 MEAN 0.165 0.182 0.158 0.181 SD 0.109 0.129 0.121 0.102 CV %66.167 70.793 76.926 56.495 GEOMETRICMEAN 0.130 0.129 0.113 0.156 MIN0.025 0.025 0.025 0.073 To calculate Cmin values on Days 7, 14, 21, and22. BLQ was input in the database with the ½ lower limit ofquantification value of 0.05 ng/ml (i.e., 0.025). During the last week,3 subjects missed applications (404 on Day 18, 407 on Day 20, and 416 onDay 17) and are excluded from Days 21 and 22 results to provide datawith subjects who applied all applications.

TABLE 140 Summary of Serum Pharmacokinetic Parameters- Cmin (ng/mL) byDay for Imiquimod, PK Population TREATMENT: IMIQUIMOD 3.75% CREAM QDANALYTE: Serum R-837 (Imiquimod) Subject ID/ Statistics Day 7 Day 14 Day21 Day 22 MEDIAN 0.142 0.181 0.137 0.145 MAX 0.480 0.467 0.467 0.370 Tocalculate Cmin values on Days 7, 14, 21, and 22, BLQ was input in thedatabase with ½ the lower limit of quantification value of 0.05 ng/ml(i.e., 0.025). During the last week, 3 subjects missed applications (404on Day 18, 407 on Day 20, and 416 on Day 17) and are excluded from Days21 and 22 results to provide data with subjects who applied allapplications.

As shown above in Table 137, imiquimod peak exposure (C_(max)) and totalexposure (AUC) increased in serum over the 21 days of once dailyapplications. Mean C_(max) increased from 0.259 ng/mL on Day 1 to 0.488ng/mT on Day 21. Between Day 1 and Day 21, mean AUC₀₋₂₄ increased from3.748 to 6.795 ng·hr/mL. Imiquimod median T_(max) was 12 hours on Days 1and 21.

Mean accumulation ratios for imiquimod reflect the increase in peak andtotal exposure between Day 1 and Day 21. The ratio of peak exposure(RE_(max)) of 2.260 and the ratio of overall systemic exposure (R_(AUC))of 2.169 indicated an approximate 2-fold increase in both peak exposureand total exposure over 21 days. The mean effective half-life foraccumulation, T_(1/2EFF), was 31.328 hours; 5 times T_(1/2EFF) dividedby 24 hours would indicate that imiquimod should reach steady state onapproximately Day 6 or 7 after repeated once daily administration.

The apparent elimination rate constant, λ_(z), was 0.0756 on Day 1 and0.0370 on Day 21. The imiquimod mean half-lives, T_(1/25) were 12.5±8.2hours on Day 1 (sampling through 24 hours) and 24.1±12.4 hours on Day 21(sampling through 72 hours). This apparent increase in half-life mostlikely represented a better estimate on Day 21 due to the longersampling duration and fewer BLQ concentrations. Five times the apparentelimination half-life measured on Day 21 divided by 24 hours indicatedthat steady-state conditions should be reached on Day 5 following oncedaily administration.

No significant differences in imiquimod (R-837) pharmacokineticparameters were observed on Day 21 when data excluding Subject 001-404(missed Day 8 and Day 18 applications), Subject 001-407 (missed Day 20application), and Subject 001-416 (missed Day 17 application) werecompared to data including these 3 subjects the inclusion/exclusion ofthese 3 subjects did not affect the conclusions.

Serum concentrations of two imiquimod metabolites (S-26704 and S-27700combined) were measured, but the data were too sparse to assess.

TABLE 141 Comparison of Female and Male Subject Non-Dose-Normalized andDose-Normalized Pharmacokinetic Parameters on Day 21 Mean (SD) Day 21Female^(a) Male^(b) Not Dose Dose Not Dose Dose Parameter N Normalized NNormalized N Normalized N Normalized C_(max) (ng/mL) 4 0.676 (0.656) 40.583 (0.484) 11 0.420 (0.203) 11 0.431 (0.198) AUC₀₋₂₄ (ng•hr/mL) 47.192 (4.796) 4 6.428 (3.791) 11 6.651 (3.327) 11 6.858 (3.351) T_(max)(hr)^(c) 4 6.50 — — 11 12.00 — — (1.00-12.00) (4.00-16.00) ^(a)Resultsdo not include Subject 001-416 (missed an application on Day 17).^(b)Results do not include Subject 001-404 (missed applications on Days8 and 18) and Subject 001-407 (missed an application on Day 20).^(c)Median (minimum-maximum)

As shown in Tables 141 and 142, when not dose normalized, peak exposure,C_(max), was 61% higher in female subjects than in male subjects (0.676versus 0.420 ng/mL), and total systemic exposure, AUC₀₋₂₄, was 8% higherin female subjects than in male subjects (7.192 versus 6.65 1 ng hr/mL).When dose normalized and reported without subjects who missed anapplication of study drug during the last week of dosing, C_(max) was35% higher in female subjects than in male subjects (0.583 versus 0.431ng/mL) while AUC₀₋₂₄ was 6% lower in female subjects than in malesubjects (6.428 versus 6.85 8 nglr/mL). Median T_(max) occurredapproximately twice as quickly in female subjects (6.50 hours) as inmale subjects (12.00 hours).

TABLE 142 Mean (SD) Cmax (ng/mL) and Mean (SD) AUC₀₋₂₄ (ng · hr/mL) DoseFemale Male Normalized (n = 4) (n = 11) Mean (SD) No 0.676 0.420 Cmax(0.656) (0.203) (ng/mL) Yes 0.583 0.431 (0.484) (0.198) Mean (SD) No7.192 6.651 AUC0-24 (4.796) (3.327) (ng · hr/mL) Yes 6.428 6.858 (3.791)(3.351)

TABLE 143 Primary Analysis of Steady State for Imiquimod Trough SerumConcentrations (PK Population) Geometric 90% Trough (Pre-Dose) GeometricLS Mean^(a) Mean Confidence Comparison N Test Reference Ratio^(b)Interval Day 14 vs. Day 7  13 0.1749 0.1543 1.1335 0.7364-1.7446 Day 21vs. Day 14 11 0.1571 0.1874 0.8384 0.5308-1.3243 Day 22 vs. Day 21 120.1839 0.1643 1.1194 0.7640-1.6402 Note: Primary steady-state analysisonly included subjects with paired and non-zero serum concentration dataon the days being compared and subjects who applied all 7 applicationsin the preceding week and applied at least 80% of the prescribedapplications in all prior weeks. ^(a)Point estimate for geometricleast-squares (LS) mean was based on an ANOVA model, including study dayas a fixed effect. ^(b)Steady-state conditions were considered to existduring an interval if the point estimate for the geometric mean ratiowas <1.43.

TABLE 144 Secondary Analysis of Steady State for Imiquimod Trough SerumConcentrations (PK Population) Geometric 90% Trough (Pre-Dose) GeometricLS Mean^(a) Mean Confidence Comparison N Test Reference Ratio^(b)Interval Day 14 vs. Day 7 17 0.1259 0.1270 0.9915 0.5876-1.6729 Day 21vs. Day 14 15 0.1127 0.1150 0.9805 0.5344-1.7992 Day 22 vs. Day 21 150.1556 0.1127 1.3800 0.8537-2.2309 Note: Secondary steady-state analysisonly included subjects with paired serum concentration data in which BLQvalues were replaced with LLOQ/2 values on the days being compared andsubjects who applied all 7 applications in the preceding week andapplied at least 80% of the prescribed applications in all prior weeks.^(a)Point estimate for geometric least-squares (LS) mean was based on anANOVA model, including study day as a fixed effect. ^(b)Steady-stateconditions were considered to exist during an interval if the pointestimate for the geometric mean ratio was <1.43.

As shown above in Tables 143 and 144 the geometric mean ratios for allsteady-state comparison intervals were <1.43, indicating that steadystate was achieved by Day 7. In the primary analysis, the geometric meanratio during the Day 21 versus Day 14 interval was lower than might beexpected (0.83 84), but the geometric mean ratio for the Day 22 versusDay 21 interval (1.1194) and the geometric mean ratio for the Day 14versus Day 7 interval (1.1335) were both close to 1.00, indicating thatsteady-state conditions were likely achieved by Day 7. This conclusionis consistent with the estimated time to steady state calculated fromthe observed mean elimination half-life and the mean effective half-lifefor accumulation. The decrease in the geometric mean ratio during theDay 21 versus Day 14 interval may have been a consequence of inpatientversus outpatient application. Overall, it appears that steady-stateconditions were achieved by Day 7.

TABLE 145 Summary of External Genital Wart Area (mm³) by Visit Compound:Imiquimod 3.75% Cream QD Protocol: GW01-0804 3.75% (N = 18) Baseline(Day 1) N 18 Mean (SD) 108.3 (138.7) Median 60.0 Minimum, Maximum 15.0,620.0 Day 7 N 18 Mean (SD) 101.3 (125.3) Minimum, Maximum 15.0, 554.0Percent Change from Baseline N 18 Mean (SD) −6.8 (20.8) Median −4.1Minimum, Maximum −59.5, 49.3 P. Value 0.1836 Day 14 N 18 Mean (SD) 73.8(59.8) Median 65.5 Minimum, Maximum 2.0, 248.0 Percent Change fromBaseline N 18 Mean (SD) −19.7 (30.3) Median −17.6 Minimum, Maximum−94.6, 42.4 P Value 0.0133 Day 21 N 18 Mean (SD) 43.2 (28,1) Median 41.5Minimum, Maximum 0.0, 90.0 Percent Change from Baseline N 18 Mean (SD)−45.0 (27.6) Median −43.0 Minimum, Maximum −100.0, 8.0 P Value <.0001Note: P values are from t-test against no change from baseline.Pharmacokinetics Conclusions

Serum concentrations of imiquimod were low in subjects with EGWs treatedwith up to one packet of imiquimod 3.75% cream once daily for 21 days.Mean serum concentrations ranged from approximately 0.16 to 0.37 ng/mLon Day 21. Serum concentrations of two imiquimod metabolites (S-26704and S-27700 combined) were measured, but the data were too sparse toassess (only 4 subjects had any concentrations above the LLOQ on Day21). In the pharmacokinetic population, imiquimod mean peak (C_(max))and total exposure (AUC₀₋₂₄) increased between Day 1 and Day 21. Theaccumulation ratios based on peak exposure, and overall systemicexposure, R_(AUC), indicated an approximate 2-fold accumulation (2.260and 2.169, respectively) at steady state. Imiquimod median T_(max) was12 hours on Days 1 and 21. The mean effective half-life foraccumulation, T_(1/2EFF), was 31.328 hours, and the observed meanelimination half-life, T^(1/2), was 24.1±2.4 hours on Day 21. Analysisof trough concentrations over time indicated that steady-stateconditions were achieved by Day 7, which was consistent with the time tosteady state predicted from the observed mean elimination half-life(approximately 5 days) and the mean effective half-life for accumulation(approximately 6 to 7 days).

On Day 21, non-dose-normalized mean peak exposure, C_(max) was 61%higher in female subjects than in male subjects and dose-normalized(adjustment for differences in dosage) mean C_(max), was 35% higher infemale subjects. Non-dose-normalized mean total systemic exposure,AUC₀₋₂₄, was 8% higher in female subjects than in male subjects whiledose-normalized mean AUC₀₋₂₄ was 6% lower in female subjects on Day 21.Median T_(max) occurred approximately twice as quickly in femalesubjects (6.5 hours) as in male subjects (12.0 hours). Due to thecontrolling influence of a single female subject and the disparity inthe number of female and male subjects (4/11), female/male comparativeresults appeared somewhat skewed, but mean C_(max) values were low forboth female and male subjects (<1.0 ng/mL) Overall, peak exposure(C_(max)) appeared higher and reached more quickly in female subjectsthan in male subjects, and total systemic exposure (AUC₀₋₂₄) appearedcomparable in female and male subjects.

Brief Summary of Adverse Events

A total of 14 treatment-emergent adverse events (TEAEs) were experiencedby 10 of 18 subjects (55.6%) treated with imiquimod 3.75% cream in thisstudy. Of the 14 TEAEs reported, 4 TEAEs experienced by 3 of 18 subjects(16.7%) were considered probably related or related totreatment—application site ulcer experienced by 2 subjects (11.1%) andapplication site irritation and application site pruritus experienced bythe same subject (5.6%). Dosing was interrupted for 2 days for 1 subject(5.6%) due to an application site ulcer. All TEAEs were mild inintensity except moderate application site ulcer experienced by 2subjects (11.1%) and moderate upper respiratory tract infectionexperienced by 1 subject (5.6%). No deaths, serious adverse events(SAEs), or discontinuations due to AEs were reported.

Analysis of Adverse Events

Approximately half the subjects, 10 of 18 (55.6%), treated with up to 1packet imiquimod 3.75% cream once daily for 21 days in this studyexperienced TEAEs. The most commonly reported TEAEs were headache in 4of 18 subjects (22.2%) and application site ulcer in 2 of 18 subjects(11.1%), All other TEAEs were experienced by 1 of 18 subjects (5.6%) andincluded vomiting, application site irritation, application sitepruritus, fatigue, upper respiratory tract infection, excoriation, andphlebitis. All of these TEAEs were mild in intensity except moderateapplication site ulcer experienced by 2 subjects (11.1%) (one male andone female) and moderate upper respiratory tract infection experiencedby 1 female subject (5.6%).

Only a small number of subjects—3 of 18 (16.7%)—experienced TEAEsconsidered probably related or related to treatment. The most frequentlyoccurring treatment-related TEAE was application site ulcer, which wasexperienced by 2 subjects (11.1%). Application site irritation (burning)and application site pruritus were experienced by the same male subject(5.6%).

Analysis of Local Skin Reactions (LSRs)

LSRs, including erythema, edema, weeping/exudate,flaking/scaling/dryness, and scabbing/crusting were evaluated forseverity (mild, moderate, or severe) on Days 1 (pre-application), 7, 14,and 21 and at 48 and 72 hours post last application. The occurrence oferosion and ulceration were also reported. The majority of LSRs weremild or moderate and were first noticeable on Day 14. Severe LSRs wereexperienced by 22.2% of the subjects (4 of 18): three experienced severeerythema, two experienced severe weeping/exudate, and one experiencedsevere scabbing/crusting (the same subject had experienced severeweeping/exudate). The only LSR reported as an adverse event was moderateulceration that required medical intervention and was considered relatedor probably related to treatment in 11.1% of the subjects (2 of 18).

Safety Conclusions

imiquimod 3.75% cream applied once daily for up to 21 days was welltolerated. Treatment-emergent adverse events (TEAEs) were experienced by10 of 18 subjects (55.6%). TEAEs considered probably related or relatedto treatment included 4 TEAEs reported by 3 of 18 subjects (16.7%):application site ulcer experienced by 2 subjects (11.1%) and applicationsite irritation and application site pruritus experienced by the samesubject (5.6%).

Dosing was interrupted for 2 days for 1 subject (5.6%) due to anapplication site ulcer. All TEAEs were mild in intensity except formoderate application site ulcer experienced by 2 subjects (11.1%) andmoderate upper respiratory tract infection experienced by 1 subject(5.6%). No deaths, SAEs, or discontinuations due to AEs were reported.

Expected local skin reactions were generally mild to moderate, observedprimarily on or after Day 14, and rarely interrupted treatment. Erythemawas the most frequently reported local skin reaction (13 of 18 subjects,72.2%), followed by edema (9 subjects, 50%); weeping/exudate andscabbing/crusting (7 subjects each, 38.9%); flaking/scaling/dryness (6subjects, 33.3%), erosion (6 subjects, 33.3%), and ulceration (5subjects, 27.8%). Overall, 7 of 18 subjects (38.9%) experienced all ormost of the local skin reactions, with 4 of these subjects (22.2%)experiencing severe reactions. LSRs generally resolved or lessened inseverity during the 72 hours after the last application of the studydrug was applied. Clinical laboratory values were generally withinreference ranges for all parameters in this study. Vital signs andphysical examinations did not reveal any significant safety concerns.

Discussion and Overall Conclusions

In this open-label, single-center, non-randomized study, pharmacokinetic(PK) and safety were evaluated in 18 subjects with at least 8 externalgenital warts (EGWs) in the genital/perianal area or a total wart areaof ≥100 mm² who applied imiquimod 3.75% cream to the affected areas oncedaily for up to 21 days.

Serum concentrations of imiquimod (R-837) were low in subjects treatedwith daily applications of imiquimod 3.75% cream (mean of 0.16 to 0.37ng/mL on Day 21). The maximum serum concentrations were 1.632 ng/mL forfemale subjects (Day 21) and 0.659 ng/mL for male subjects (Day 22).Serum concentrations of two imiquimod metabolites (S-26704 and S-27700combined) were measured, but the non-zero data were too sparse toassess.

Peak exposure (C_(max)) and total exposure (AUC₀₋₂₄) for imiquimod(R-837) were higher on Day 21 than Day 1 when analyzing all subjects inthe pharmacokinetic population except 3 subjects who missed anapplication during the last week of dosing. The mean accumulationratios, R_(Cmax) and R_(AUC), were 2.260 and 2.169, respectively. On Day21, the serum concentration profile showed minor fluctuations during the24 hours after application—mean C_(max) (0.488±0.368 ng/mL) wasapproximately 3 times the level of mean C_(min) (0.158±0.121 ng/mL).Imiquimod (R-837) median T_(max) was 12 hours on Days 1 and 21. The meaneffective half-life for accumulation was 31.33 hours, and the observedmean elimination half-life was 24.14 hours on Day 21. Analysis of troughconcentrations over time indicated that steady-state conditions wereachieved by Day 7, which was consistent with the time to steady statepredicted from the mean observed elimination half-life (approximately 5days) and the mean effective half-life for accumulation (approximately 6or 7 days).

In a comparison of female and male subjects who applied imiquimod 3.75%cream to EGWs, analyses of the female and male groups were limited bywide variability in the data, small overall numbers, a large disparityin group sizes (female/male comparison of 4 versus 11 subjects), and thecontrolling influence of a single female subject. Dose normalization wasemployed to adjust for differences in dosage. When not dose normalized,mean C_(max) was 61% higher in female subjects than in male subjects,and mean AUC₀₋₂₄ was 8% higher in female subjects than in male subjects.When dose normalized, mean Cm. was 35% higher in female subjects than inmale subjects while mean AUC₀₋₂₄ was 6% lower in female subjects than inmale subjects. Overall, mean C_(max) and AUC₀₋₂₄ were low and generallycomparable on Day 21 for female subjects, male subjects, and the entirepharmacokinetic population—mean C_(max): 0.583, 0.431, and 0.488 ng/mL,respectively, and mean AUC₀₋₂₄: 6.428, 6.858, and 6.795 ng/hr/mL,respectively. Median T_(max) occurred approximately twice as quickly infemale subjects (6.50 hours) as in male subjects (12.00 hours).

Safety evaluations demonstrated that imiquimod 3.75% cream was welltolerated when applied once daily for up to 21 days. Treatment-emergentadverse events (TEAEs) were experienced by 10 of 18 subjects (55.6%),and all but 3 of the TEAEs were mild moderate application site ulcerexperienced by 2 subjects (11.1%) and moderate upper respiratory tractinfection experienced by 1 subject (5.6%). Only 3 subjects (16.7%)experienced TEAEs that were considered probably related or related totreatment application site ulcer experienced by 2 subjects (11.1%) andapplication site irritation and application site pruritus experienced bythe same subject (5.6%). Dosing was interrupted for 2 days for 1 subject(5.6%) due to an application site ulcer. The TEAEs observed in thisstudy were consistent with TEAEs previously observed with the currentlymarketed 5% imiquimod cream product (Aldara®).⁷ No deaths, SAEs, ordiscontinuations due to AEs were reported.

Expected local skin reactions were generally mild to moderate and wereobserved primarily on or after Day 14. Erythema was the most frequentlyreported local skin reaction (13 of 18 subjects, 72.2%), followed byedema (9 subjects, 50%); weeping/exudate and scabbing/crusting (7subjects each, 38.9%); flaking/scaling/dryness (6 subjects, 33.3%),erosion (6 subjects, 33.3%), and ulceration (5 subjects, 27.8%).Overall, 7 of 18 subjects (38.9%) experienced all or most of the localskin reactions, with 4 of these subjects (22.2%) experiencing severereactions. Once observed during treatment, an LSR appeared to eitherlast 1 week, or if persisting, often continued throughout the study at alower severity. LSRs generally resolved or lessened in severity duringthe 72 hours after the last application of the study drug was applied.No severe LSRs were observed at the end of the, study (the visit at 72hours after the last application of the study cream).

Clinical laboratory values, vital signs, and physical examinations didnot reveal any significant safety concerns.

In conclusion, the amount of imiquimod (R-837) absorbed into systemiccirculation after topical application of imiquimod 3.75% cream toexternal genital warts once daily for up to 21 days was low; C_(max)(peak exposure) and AUC₀₋₂₄ (total systemic exposure) increasedapproximately 2-fold between Day 1 and Day 21. T^(1/2), was 12.5±8.2hours on Day 1 (sampling through 24 hours) and 24.1±12.4 hours on Day 21(sampling through 72 hours). Steady state was achieved by Day 7. Peakexposure (C_(max)) appeared higher and reached more quickly (C_(max)) infemale subjects than in male subjects, and total systemic exposure(AUC₀₋₂₄) appeared comparable in female and male subjects. The degree ofdifference in results between female and male subjects did not indicateany reason for safety concerns.

Imiquimod 3.75% cream applied to external genital warts once daily forup to 21 days was well-tolerated. Treatment-related adverse events onlyoccurred in a small percentage of subjects (16.7%), and with theexception of three of moderate intensity, all treatment-emergent adverseevents were mild. The majority of local skin reactions were generallymild to moderate in intensity and were observed primarily on or afterDay 14. Severe reactions were only observed for erythema in 3 subjects,weeping/exudate in 2 subjects, and scabbing/crusting in 1 subject.

Example 27

Study of in vitro Effects of Imiquimod on QT, QRS, APD, Tp-e andArrhythmogenesis in Rabbit Left Ventricular Wedge Preparation

1. Drug and Concentrations Tested

Imiquimod (n=6, MW 240): 0.5 nM, 5 nM, 50 nM and 150 nM. Cisapride as apositive control compound (n=4, MW 483.96): 5 nM, 50 nM, 150 nM and 500nM.

2. Objectives

The purpose of this project was to examine the effects of imiquimod onQRS duration, QT interval, T_(p-e), interval, an index of transmuraldispersion of repolarization and proarrhythmias including early afterdepolarization (EAD) in the isolated rabbit left ventricular wedgepreparation. In addition, the relative TdP risk of imiquimod wasestimated using a score table. More importantly, the effects ofimiquimod were compared with those of a positive control cisapride,which has been reported to induce QT prolongation and Torsades dePointes (TdP).

3. Materials and Methods

3.1 Arterially Perfused Rabbit Left Ventricular Wedge Preparations

New Zealand White rabbits, either sex weighing 2.3-2.8 kg wereanticoagulated with heparin and anesthetized with ketamine/xylazine(40-50 mg/0.5-1.0 mg, per kg, i.v.). The chest was opened via a leftthoracotomy, and the heart was excised and placed in a cardioplegicsolution consisting of cold (4° C.) normal Tyrode's solution. Transmuralwedges with dimensions of approximately 1.5 cm wide and 2-3 cm long weredissected from the left ventricle as described before (Liu et al, HeartRhythm 2006; 3:948-956). The tissue was cannulated via a small branch ofthe left anterior descending artery and perfused with cardioplegicsolution. The preparation was then placed in a small tissue bath andarterially perfused with Tyrode's solution containing 4 mM K+ bufferedwith 95% 02 and 5% CO2 (Temperature: 35.7±0.1° C., perfusion pressure:40-50 mmHg). The ventricular wedge was allowed to equilibrate in thetissue bath until electrically stable for one hour. The preparationswere stimulated at basic cycle lengths (BCL) of 1000 and 2000 ms usingbipolar silver electrodes insulated except at the tips and applied tothe endocardial surface.

3.2 Electrophysiologic Recordings from Rabbit Ventricular WedgePreparations

A transmural ECG signal was recorded via a HP ECG amplifier (model8811A) using extracellular silver/silver chloride electrodes placed inthe Tyrode's solution, bathing the preparation 1.0 to 1.5 cm from theepicardial and endocardial surfaces, along the same vector as thetransmembrane recordings (Epi: “+” pole). The QT interval was defined asthe time from the onset of the QRS to the point at which the finaldownslope of the T wave crosses the isoelectric line. Transmembraneaction potential from the endocardium (Endo) was recorded foridentification of EADs only when QT prolongation >30% via acustomer-made amplifier. Transmural dispersion of repolarization (TDR)was defined as the interval between the end and the peak of T wave(T_(p-e)).

All measured biological signals including ECG and transmembrane actionpotentials were sampled via a D/A converter (CED 1401, England) andstored in electronic media (CD) and external hard drives. The rawsignals of ECG and transmembrane action potentials were analysed usingSpike 2 software (CED, England).

3.3 Formulation

Imiquimod and cisapride in dimethyl sulfoxide (DMSO) were prepared oneach experimental day. The maximal concentration of DMSO was ≤0.1%.

3.4 Study Designs

-   -   (1) Imiquimod was tested at concentrations of 0.5 nM, 5 nM, 50        nM and 150 nM in 6 wedge preparations. The positive control        cisapride was tested in 5 nM, 50 nM, 150 nM and 500 nM in 4        wedge preparations.    -   (2) The preparation was exposed to imiquimod and cisapride at        each concentration for ≥30 minutes.    -   (3) Two BCLs of 1000 and 2000 ms were used.    -   (4) Action potentials from Endo in the rabbit wedge preparation        were recorded for identification of EAD-dependent phenomena only        when QT prolongation was greater than 30%.    -   (5) The QT and QRS intervals and the interval of T_(p-e), an        index of transmural dispersion of repolarization (TDR), were        measured. The ratio of T_(p-e) to QT was calculated.    -   (6) Arrhythmic phenomena, including spontaneous R-on-T ectopic        beats and TdP, were recorded if they occurred.        3.5 To Estimate Relative TdP Risk

The relative TdP risk of each compound was estimated according in whichthe T_(p-e)/QT ratio and LAD-dependent phenomena were emphasized.

3.6 Data Analysis

Results were presented as mean±SEM. Statistical analysis was performedusing the Student's t-test. A p<0.05 is considered as statisticallysignificant when compared the values at control perfusion.

4. Results

4.1 Effect on QRS Duration

Imiquimod had no significant effect on QRS duration in the concentrationranges tested.

On the other hand, the positive control cisapride produced a small butstatistically significant increase in QRS duration at concentration of0.5 uM.

4.2 Effects on QT

Imiquimod exhibited a trend to produce a small QT increase (4%) atconcentrations of 150 nM only at a BCL of 2000 ms. However, previousvalidation data (data from Main Line Health Heart Center) using DMSO asa vehicle control group revealed comparable QT prolongation. There wasno statistical significance in QT between imiquimod and vehicle groups.

On the other hand, the positive control drug cisapride exhibited markedconcentration-dependent QT prolongation.

4.3 Effects on T_(p-e), Interval

Imiquimod had no significant effect on T_(p-e) Interval in theconcentration range tested (n=6).

On the other hand, the positive control drug cisapride exhibited markedconcentration-dependent T_(p-e) prolongation.

4.4 Proarrhythmias

Imiquimod did not cause any proarrhythmic events in any preparation atany concentration. The estimated TdP scores are either zero or negative.

Cisapride caused an equivocal EAD in 1 of 4 preparations atconcentration of 0.5 uM. Its maximal TdP score is 6.5±0.5 atconcentration of 0.5 uM.

5. Comments and Conclusions

Imiquimod does not have a significant effect on the QT interval, T_(p-e)(an index of transmural dispersion of repolarization) and QRS,indicating that imiquimod possesses little risk of TdP (TdP score<0) andother proarrhythmias like ventricular tachycardia in the concentrationrange tested.

The positive control Cisapride produced marked concentration-dependentQT and T_(p-e) prolongation in the concentration range from 0.005 to 0.5uM. The maximal TdP score in the rabbit left ventricular wedgepreparation is 6.5. This indicates that the rabbit left ventricularwedge preparation has a sufficient sensitivity to detect even a weak QTprolonging liability.

Thus, this clinical case as summarized in Examples 24-26 and asillustrated in FIGS. 1-36, further demonstrates efficacy withouttreatment limiting local skin reactions or adverse events and furtherdemonstrates that complete clearance is achieved with a 3.75% imiquimodformulation of Example 23 when applied to the treatment areas diagnosedwith EGWs of a subject following a treatment regimen described in thoseExamples 24-26. In Example 23 herein above, formulations 126 and 182,wherein the fatty acid is isa, are the formulations that are used inExamples 24-26 and in FIGS. 1-36 discussed and described herein above.In addition, isa formulations 126 and 182 pass the PET tests when storedat about 40° C. for about 3 months.

The following are a draft of the U.S. Label and the Canadian ProductMonograph referenced in Example 25 above.

Draft U.S. Label (referred to in Example 25)

Highlights of Prescribing Information

These highlights do not include all the information needed to useZyclara™ safe effectively. See full prescribing information for ZyclaraCream.

ZYCLARA (imiquimod), Cream, 3.75%

For topical use only

Initial U.S. Approval:

Indications and Usage

Zyclara Cream is indicated for the treatment of external genital andperianal warts/condyloma acuminate in patients 12 years or older (11)

Dosage and Administration

Zyclara Cream is not for oral, opthamalic, intra-anal or intravaginaluse. (2)

-   -   External Genital Warts: daily to the external genital/perianal        warts until total clearance or up to 8 weeks (2.1)        Dosage Forms and Strengths

Zyclara (imiquimod Cream, 3.75% is supplied in single-use packets (28per Dose Pack), each of which contains 250 mg or the cream, equivalentto 9.4 mg of imiquimod. (3)

Contraindictions

-   -   None (4)        Warnings and Precautions    -   Intense local inflammatory reactions can occur (e.g. skin        weeping, erosion). Dosing interruption may be required (2, 5.1,        6)    -   Flu-like signs and symptoms way accompany or even precede, local        skin reactions, and may include fatigue, fever, myalgia, malaise        and nausea. Dosing interruption may be required (2, 5.2, 6)    -   Avoid exposure to sunlight and sunlamps to the affected areas        (5.3).    -   Treatment of urethral, intra-vaginal, cervical, rectal or        intra-anal viral disease is not recommended. (5.)        Adverse Reactions

Table 1: Local Skin Reactions in the Treatment Area Assessed by theInvestigator; Table 1: Local Skin Reactions in the Treatment AreaAssessed by the Investigator Table 2: Treatment Related AdverseReactions Occurring in >1% of Zyclara-Treated Subjects and at a GreaterFrequency that with Placebo in either gender. (6)

To report SUSPECTED ADVERSE REACTIONS, contact Graceway Pharmaceuticals,LLC at 1-800-328-0255 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patientlabeling.

Full Prescribing Information: Contents* *Sections or subsections omittedfrom the Full Prescribing information are not listed.

1. INDICATIONS AND USAGE

-   -   1.1 Unevaluated Populations

2. DOSAGE AND ADMINISTRATION

3. DOSAGE FORMS AND STRENGTHS

4. CONTRAINDICTIONS

5. WARNINGS AND PRECAUTIONS

-   -   5.1 Local Skin Reactions    -   5.2 Systemic Reactions    -   5.3 Ultraviolet Light Exposure    -   5.4 Unevaluated Uses: External Genital Warts

6. ADVERSE REACTIONS

-   -   6.1 Clinical Trials Experience    -   6.2 Dermal Safety Trials Experience    -   6.3 Postmarketing Experience

7. USE IN SPECIFIC POPULATIONS

-   -   8.1 Pregnancy    -   8.3 Nursing Mothers    -   8.4 Pediatric Use    -   8.5 Geriatric Use        Overdosage        Description        Clinical Pharmacology    -   12.1 Mechanism of Action    -   12.2 Pharmacodynamics    -   12.3 Pharmacokinetics        Nonclinical Toxicology    -   13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

8. CLINICAL STUDIES

How Supplied/storage and Handling

Patient Counseling Information

-   -   17.1 Instructions for Administration    -   17.2 Local Skin Reactions    -   17.3 Systemic Reactions    -   17.4 Recommended Administration    -   17.7 FDA—Approved Patient Labeling

Full Prescribing Information

1 INDICATIONS AND USAGE

Zyclara Cream is indicated for the treatment of external genital andperianal warts/condyloma acuminata, whether present at the start oftherapy or emerging during therapy, in patients 12 years or older.

1.1 Unevaluated Populations

The safety and efficacy of Zyclara Cream in immunosuppressed patientshave not been established.

Zyclara Cream should be used with caution in patients with pre-existingautoimmune conditions.

2 Dosage and Administration

Zyclara Cream is not for oral, ophthalmic, infra-anal, or intravaginaluse. Zyclara Cream should be applied once-a-day to the externalgenital/perianal warts. Zyclara Cream should be used for up to 8 weeks.Zyclara Cream should be applied prior to normal sleeping hours and lefton the skin for approximately 8 hours, after which time the cream shouldbe removed by washing the area with mild soap and water. The prescribershould demonstrate the proper application technique to maximize thebenefit of Zyclara Cream therapy.

It is recommended that patients wash their hands before and afterapplying Zyclara Cream.

A thin layer of Zyclara Cream should be applied to the areas of existingand emerging warts and rubbed in until the cream is no longer visible.The application site should not be occluded. Following the treatmentperiod the cream should be removed by washing the treated area with mildsoap and water.

Local skin reactions at the treatment site are common. [see AdverseReactions (6.2)] A rest period of several days may be taken if requiredby the patient's discomfort or severity of the local skin reaction.Treatment may resume once the reaction subsides. Non-occlusive dressingssuch as cotton gauze or cotton underwear may be used in the managementof skin reactions.

Zyclara Cream is packaged in single-use packets with 28 packets suppliedper box, which contain sufficient cream to cover the wart areas; use ofexcessive amounts of cream should be avoided. Patients should beprescribed no more than 2 Dose Packs (56 packets) for the treatmentcourse. Unused packets should be discarded. Partially-used packetsshould be discarded and not reused.

3 Dosage Forms and Strengths

Zyclara (imiquimod) Cream, 3.75%, is supplied in single-use packets eachof which contains 250 mg of the cream, equivalent to 9.4 mg ofimiquimod. Zyclara Cream is supplied in a Dose Pack of 28 packets each.

4 Contraindications

None.

5 Warnings and Precautions

5.1 Local Skin. Reactions

Intense local skin reactions including skin weeping or erosion can occurafter a few applications of Zyclara Cream and may require aninterruption of dosing. [see Dosage and Administration (2) and AdverseReactions (6)]. Zyclara Cream has the potential to exacerbateinflammatory conditions of the skin, including chronic graft versus hostdisease.

Administration of Zyclara Cream is not recommended until the skin ishealed from any previous drug or surgical treatment.

5.2 Systemic Reactions

Flu-like signs and symptoms may accompany, or even precede, local skinreactions and may include fatigue, fever, myalgia, malaise and nausea.An interruption of dosing and an assessment of the patient should beconsidered. [see Adverse Reactions (6)]

5.3 Ultraviolet Light Exposure

In an animal photo-carcinogenicity study, imiquimod cream shortened thetime to skin tumor formation [see Nonclinical Toxicology (13.1)]. Theenhancement of ultraviolet carcinogenicity is not necessarily dependenton phototoxic mechanisms. Therefore, patients should minimize or avoidnatural or artificial sunlight exposure to the affected areas.

5.4 Unevaluated Uses

Zyclara Cream has not been evaluated for the treatment of urethral,intra-vaginal, cervical, rectal, or intra-anal human papilloma viraldisease.

6 Adverse Reactions

Clinical trials are conducted under widely varying conditions. Adversereaction rates observed in the clinical trials of a drug cannot bedirectly compared to rates in the clinical trials of another drug andmay not reflect the rates observed in practice.

6.1 Clinical Trials Experience

In two double-blind, placebo-controlled studies for genital warts, 602subjects applied up to one packet of Zyclara Cream or placebo daily forup to 8 weeks. The most frequently reported adverse reactions were localskin and application site reactions.

Overall, fewer than 1% (3/400) of the subjects treated with Zyclaracream discontinued due to local skin/application site reactions. Theincidence and severity of local skin reaction during controlled clinicalstudies are shown in Table 1 below.

TABLE 1 Local Skin Reactions in the Treatment Area Assessed by theInvestigator Zyclara Cream Placebo Females Males Females Males n = 217 n= 183 n = 106 n = All All All All All Grades* Severe Grades* SevereGrades* Severe Grades* Severe Erythema 74% 10% 78% 10% 23%  0% 37%  1%Edema (induration) 41%  2% 48%  2% 8% 0% 9% 0% Weeping/Exudate 35%  1%39%  3% 5% 0% 0% 0% Flaking/Scaling/ 26%  0% 39%  0% 11%  0% 11%  0%Dryness Scabbing/Crusting 18% <1% 34%  1% 6% 0% 2% 0% Erosion/Ulceration36% 13% 42% 10% 7% 1% 2% 0% *Mild, Moderate, or Severe

Local skin reactions were recorded as adverse events if they extendedbeyond the treatment area, if they required any medical intervention, orthey resulted in patient discontinuation from the study.

Selected treatment related adverse reactions are listed below.

TABLE 2 Treatment Related Adverse Reactions Occurring in >1% ofZyclara-Treated Subjects and at a Greater Frequency than with Placebo ineither gender Females Males Zyclara Zyclara Cream Placebo Cream PlaceboPreferred Term n = 217 n = 106 n = 183 n = 96 Application site pain 7.8%  0% 5.5% 1.0% Application site irritation 5.5% 0.9% 6.0% 1.0%Application site pruritus 3.2% 1.9% 1.6%   0% Application site bleeding1.4% 0.9% 1.5%   0% Application site discharge 1.4%   0% 0.5%   0%Application site erythema 1.4%   0%   0%   0% Application site reaction0.9%   0% 1.1%   0% Application site rash 0.9%   0% 1.1%   0% Scrotalpain   0%   0% 1.6%   0% Application site excoriation   0%   0% 1.1%  0% Secretion discharge   0%   0% 1.1%   0% Scrotal erythema   0%   0%1.1%   0% Scrotal ulcer   0%   0% 1.1%   0% Scrotal edema   0%   0% 1.1%  0% Pruritus genital   0%   0% 1.1%   0% Application site cellulitis  0%   0% 1.1%   0%

Systemic adverse reactions considered treatment related in clinicaltrials involving Zyclara Cream included pain, pyrexia (fever),influenza, and myalgia.

Adverse reactions seen in clinical trials for external genital wartsinvolving 5% imiquimod cream included: tinea cruris, application sitesoreness, hypopigmentation, sensitivity, stinging and tenderness.

Other systemic adverse reactions considered treatment related inclinical trials for external genital warts involving 5% imiquimod creamincluded: headache, influenza-like symptoms, fatigue, malaise, nausea,and diarrhea.

6.2 Dermal Safety Trials Experience

Provocative repeat insult patch test studies involving induction andchallenge phases produced no evidence that imiquimod cream causesphotoallergenicity or contact sensitization in healthy skin; however,cumulative irritancy testing revealed the potential for imiquimod creamto cause irritation, and application site reactions were reported in theclinical studies. [see Adverse Reactions (6)]

6.3 Postmarketing Experience

The following adverse reactions have been identified duringpost-approval use of Aldara (imiquimod) Cream, 5%©. Because thesereactions are reported voluntarily from a population of uncertain size,it is not always possible to reliably estimate their frequency orestablish a causal relationship to drug exposure.

-   Application Site Disorders: tingling at the application site.-   Body as a Whole: angioedema.-   Cardiovascular: capillary leak syndrome, cardiac failure,    cardiomyopathy, pulmonary edema, arrhythmias (tachycardia, atrial    fibrillation, palpitations), chest pain, ischemia, myocardial    infarction, syncope.-   Endocrine: thyroiditis.-   Gastro-Intestinal System Disorders: abdominal pain.-   Hematological: decreases in red cell, white cell and platelet counts    (including idiopathic thrombocytopenic purpura), lymphoma.-   Hepatic: abnormal liver function.-   Infections and Infestations: herpes simplex.-   Musculo-Skeletal System Disorders: arthralgia.-   Neuropsychiatric: agitation, cerebrovascular accident, convulsions    (including febrile convulsions), depression, insomnia, multiple    sclerosis aggravation, paresis, suicide.-   Respiratory: dyspnea.-   Urinary System Disorders: proteinuria.-   Skin and Appendages: exfoliative dermatitis, erythema multiforme,    hyperpigmentation, hypertrophic scar.-   Vascular: Henoch-Schonlein purpura syndrome.    8 Use in Specific Populations    8.1 Pregnancy

Pregnancy Category C:

There are no adequate and well-controlled studies in pregnant women.Zyclara Cream should be used during pregnancy only if the potentialbenefit justifies the potential risk to the fetus.

Note: The animal multiples of human exposure calculations were based ondaily dose comparisons in this label. For the animal multiple of humanexposure ratios presented in this label, the Maximum Recommended HumanDose (MRHD), was set at 1 packet (250 mg cream) per treatment of ZyclaraCream (imiquimod 3.75%, 9.375 mg imiquimod).

Systemic embryofetal development studies were conducted in rats andrabbits. Oral doses of 1, 5 and 20 mg/kg/day imiquimod were administeredduring the period of organogenesis (gestational days 6-15) to pregnantfemale rats. In the presence of maternal toxicity, fetal effects notedat 20 mg/kg/day (375×MRHD based on AUC comparisons) included increasedresorptions, decreased fetal body weights, delays in skeletalossification, bent limb bones, and two fetuses in one litter (2 of 1567fetuses) demonstrated exencephaly, protruding tongues and low-set ears.No treatment related effects on embryofetal toxicity or teratogenicitywere noted at 5 mg/kg/day (73×MRHD based on AUC comparisons)

Intravenous doses of 0.5, 1 and 2 mg/kg/day imiquimod were administeredduring the period of organogenesis (gestational days 6-18) to pregnantfemale rabbits. No treatment related effects on embryofetal toxicity orteratogenicity were noted at 2 mg/kg/day (2.1×MRHD based on BSAcomparisons), the highest dose evaluated in this study, or 1 mg/kg/day(234×MRHD based on AUC comparisons).

A combined fertility and peri- and post-natal development study wasconducted in rats. Oral doses of 1, 1.5, 3 and 6 mg/kg/day imiquimodwere administered to male rats from 70 days prior to mating through themating period and to female rats from 14 days prior to mating throughparturition and lactation. No effects on growth, fertility, reproductionor post-natal development were noted at doses up to 6 mg/kg/day (50×MRHDbased on AUC comparisons), the highest dose evaluated in this study. Inthe absence of maternal toxicity, bent limb bones were noted in the Flfetuses at a dose of 6 mg/kg/day (50×MRHD based on AUC comparisons).This fetal effect was also noted in the oral rat embryofetal developmentstudy conducted with imiquimod. No treatment related effects onteratogenicity were noted at 3 mg/kg/day (24×MRHD based on AUCcomparisons).

8.3 Nursing Mothers

It is not known whether imiquimod is excreted in human milk followinguse of Zyclara Cream. Because many drugs are excreted in human milk,caution should be exercised when Zyclara Cream is administered tonursing women.

8.4 Pediatric Use

Safety and efficacy in patients with external genital/perianal wartsbelow the age of 12 years have not been established.

8.5 Geriatric Use

Of the 399 subjects treated with Zyclara Cream in the EGW clinicalstudies, 5 subjects (1%) were 65 years or older. Data were too sparse toevaluate treatment effects in this population. No other clinicalexperience has identified differences in responses between the elderlyand younger subjects, but greater sensitivity of some older individualscannot be ruled out.

10 Overdosage

Topical overdosing of Zyclara Cream could result in an increasedincidence of severe local skin reactions and may increase the risk forsystemic reactions.

The most clinically serious adverse event reported following multipleoral imiquimod doses of >200 mg (equivalent to imiquimod content of >21packets of Zyclara) was hypotension, which resolved following oral orintravenous fluid administration.

11 Description

Zyclara Cream is a toll-like receptor agonist for topicaladministration. Each gram contains 37.5 mg of imiquimod in an off-whiteoil-in-water vanishing cream base consisting of isostearic acid, cetylalcohol, stearyl alcohol, white petrolatum, polysorbate 60, sorbitanmonostearate, glycerin, xanthan gum, purified water, benzyl alcohol,methylparaben, and propylparaben.

Chemically, imiquimod is 1-(2-methylpropyl)-1H-imidazo [4,5-c]quinolin-4-amine. Imiquimod has a molecular formula of Cid-116N.; and amolecular weight of 240.3. Its structural formula is:

12 Clinical Pharmacology12.1 Mechanism of Action

The mechanism of action of Zyclara Cream is unknown.

12.2 Pharmacodynamics

Imiquimod has no direct antiviral activity in cell culture. A study in22 subjects with genital/perianal warts comparing imiquimod cream 5% andvehicle shows that imiquimod induces mRNA encoding cytokines includinginterferon-α at the treatment site. In addition HPVL1 mRNA and HPV DNAare significantly decreased following treatment. However, the clinicalrelevance of these findings is unknown.

12.3 Pharmacokinetics

Systemic absorption of imiquimod (up to 9.4 mg [one packet]) across theaffected skin of 18 subjects with EGW was observed with once dailydosing for 3 weeks. The mean peak serum drug concentration at Day 21 was0.488 ng/mL.

13 Nonclinical Toxicology

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

In an oral (gavage) rat carcinogenicity study, imiquimod wasadministered to Wistar rats on a 2×/week (up to 6 mg/kg/day) or daily (3mg/kg/day) dosing schedule for 24 months. No treatment related tumorswere noted in the oral rat carcinogenicity study up to the highest dosestested in this study of 6 mg/kg administered 2×/week in female rats(50×MRHD based on AUC comparisons), 4 mg/kg administered 2×/week in malerats (40×MRHD) or 3 mg/kg administered 7×/week to male and female rats(25×MRHD).

In a dermal mouse carcinogenicity study, imiquimod cream (up to 5mg/kg/application imiquimod or 0.3% imiquimod cream) was applied to thebacks of mice 3×/week for 24 months. A statistically significantincrease in the incidence of liver adenomas and carcinomas was noted inhigh dose male mice compared to control male mice (96×MIRED based on AUCcomparisons). An increased number of skin papillomas was observed invehicle cream control group animals at the treated site only.

In a 52-week dermal photo-carcinogenicity study, the median time toonset of skin tumor formation was decreased in hairless mice followingchronic topical dosing (3×/week; 40 weeks of treatment followed by 12weeks of observation) with concurrent exposure to UV radiation (5 daysper week) with vehicle alone. No additional effect on tumor developmentbeyond the vehicle effect was noted with the addition of the activeingredient, imiquimod, to the vehicle cream.

Imiquimod revealed no evidence of mutagenic or clastogenic potentialbased on the results of five in vitro genotoxicity tests (Ames assay,mouse lymphoma L5178Y assay, Chinese hamster ovary cell chromosomeaberration assay, human lymphocyte chromosome aberration assay and SHEcell transformation assay) and three in vivo genotoxicity tests (rat andhamster bone marrow cytogenetics assay and a mouse dominant lethaltest).

Daily oral administration of imiquimod to rats, throughout mating,gestation, parturition and lactation, demonstrated no effects on growth,fertility or reproduction, at doses up to 57×MRHD based on AUCcomparisons.

Clinical Studies

In two double-blind, randomized, placebo-controlled clinical studies,601 subjects with EGW were treated with 3.75% imiquimod cream, or amatching placebo cream. Studies enrolled subjects aged from 15 to 81years. The baseline wart area ranged from 6 to 5579 mm² and the baselinewart count ranged from 2 to 48 warts. Most subjects had two or moretreated anatomic areas at Baseline. Anatomic areas included: inguinal,perineal, and perianal areas (both genders); the glans penis, penisshaft, scrotum, and foreskin (in men); and the vulva (in women). Up toone packet of study cream was applied once daily to each wart identifiedat Baseline and any new wart that appeared during the treatment period.The study cream was applied to all warts prior to normal sleeping hoursand left on for approximately 8 hours. Subjects continued applying thestudy cream for up to 8 weeks or until they achieved complete clearanceof all (baseline and new) warts in all anatomic areas. Subjects notachieving complete wart clearance by the Week 8 visit (end of treatment,EOT), were evaluated for up to 8 weeks or until they achieved completeclearance during an additional 8 week no-treatment period. Subjects whoachieved complete clearance of all warts at any time until the Week 16visit entered a 12 week follow-up for recurrence period.

Efficacy was assessed by wart counts (those present at Baseline and newwarts appearing during the study) at EOS (i.e., up to 16 weeks fromBaseline).

Complete clearance required clearance of all warts in all anatomicareas. Partial clearance rate was defined as the proportion of subjectswith at least a 75% reduction in the number of baseline warts at EOS.Percent reductions were measured relative to the numbers of warts atBaseline. Complete and partial clearance rates, and percent reductionsin wart counts from baseline are shown in the table below (by overallrate and by gender).

TABLE 3 Efficacy Endpoints Zyclara Cream Placebo 3.75% Cream CompleteClearance Rate Overall 28.3% (113/399) 9.4% (19/202) Females 36.6%(79/216) 14.2% (15/106) Males 18.6% (34/183) 4.2% (4/96) PartialClearance Rate Overall 38.3% (153/399) 11.9% (24/202) Females 47.7%(103/216) 17.0% (18/106) Males 27.3% (50/183) 6.3% (6/96) PercentReduction of EGW (Median) Overall 50.0% 0.0 Females 70.7% 0.0 Males23.3% 0.0

The numbers of subjects who remained clear of EGW at the end of 12 weekfollow-up for recurrence period are shown in Table 4 below:

TABLE 4 Sustained Complete Clearance Zyclara Cream Placebo 3.75% CreamCleared and entered Follow-up 102 13 Remained Clear 71 1216 How Supplied/storage And Handling

Zyclara (imiquimod) Cream, 3.75%, is supplied in single-use packetswhich contain 250 mg of the cream. Available as: Dose Pack of 28 packetsNDC 29336-710-28. Store at 25° C. (77° F.); excursions permitted to 15°to 30° C. (59° to 86° F.) [See USP Controlled Room Temperature].

Avoid Freezing.

Keep out of reach of children.

17 Patient Counseling Information

See FDA-Approved Patient Labeling (17.7)

17.1 Instructions for Administration:

Zyclara Cream should be used as directed by a physician. [see Dosage andAdministration (2)] Zyclara Cream is for external use only. Contact withthe eyes, lips and nostrils should be avoided. [see Indications andUsage (1) and Dosage and Administration (2)].

The treatment area should not be bandaged or otherwise occluded.Partially-used packets should be discarded and not reused. Theprescriber should demonstrate the proper application technique tomaximize the benefit of Zyclara Cream therapy.

It is recommended that patients wash their hands before and afterapplying Zyclara Cream.

17.2 Local Skin Reactions:

Patients may experience local skin reactions during treatment withZyclara Cream. Potential local skin reactions include erythema, edema,erosions/ulcerations, weeping/exudate, flaking/scaling/dryness, andscabbing/crusting. These reactions can range from mild to severe inintensity and may extend beyond the application site onto thesurrounding skin. Patients may also experience application sitereactions such as itching, irritation or pain. [see Adverse Reactions(6)]

Local skin reactions may be of such an intensity that patients mayrequire rest periods from treatment. Treatment with Zyclara Cream can beresumed after the skin reaction has subsided, as determined by thephysician. Treatment should not be extended beyond 8 weeks due to misseddoses or rest periods. Patients should contact their physician promptlyif they experience any sign or symptom at the application site thatrestricts or prohibits their daily activity or makes continuedapplication of the cream difficult.

Because of local skin reactions, during treatment and until healed, thetreatment area is likely to appear noticeably different from normalskin. Localized hypopigmentation and hyperpigmentation have beenreported following use of imiquimod cream. These skin color changes maybe permanent in some patients.

17.3 Systemic Reactions:

Patients may experience flu-like systemic signs and symptoms duringtreatment with Zyclara Cream. Systemic signs and symptoms may includefatigue, fever, myalgia, malaise, and nausea. [see Adverse Reactions(6)] An interruption of dosing and assessment of the patient should beconsidered.

17.4 Recommended Administration

Dosing is once daily before bedtime to the skin of the affected wartareas. Zyclara Cream treatment should continue until there is totalclearance of the genital/perianal warts or for up to 8 weeks.

It is recommended that the treatment area be washed with mild soap andwater approximately 8 hours following Zyclara Cream application.

It is common for patients to experience local skin reactions such aserythema, erosion, excoriation/flaking, and edema at the site ofapplication or surrounding areas. Most skin reactions are mild tomoderate.

Sexual (genital, anal, oral) contact should be avoided while ZyclaraCream is on the skin. Application of Zyclara Cream in the vagina isconsidered internal and should be avoided. Female patients should takespecial care if applying the cream at the opening of the vagina becauselocal skin reactions on the delicate moist surfaces can result in painor swelling, and may cause difficulty in passing urine.

Uncircumcised males treating warts under the foreskin should retract theforeskin and clean the area daily.

New warts may develop during therapy, as Zyclara Cream is not a cure.

The effect of Zyclara Cream on the transmission of genital/perianalwarts is unknown. Zyclara Cream may weaken condoms and vaginaldiaphragms, therefore concurrent use is not recommended.

Should severe local skin reaction occur, the cream should be removed bywashing the treatment area with mild soap and water.

17.7 FDA-Approved Patient Labeling

17.8 Patient Information

-   -   Zyclara [imiquimod] Cream, 3.75%    -   (Imiquimod)        IMPORTANT: Not for Mouth, Eye, or Vaginal Use

Read the Patient Information that comes with Zyclara Cream before youstart using it and each time you get a refill. There may be newinformation. This leaflet does not take the place of talking with yourhealthcare provider about your medical condition or treatment. If you donot understand the information, or have any questions about ZyclaraCream, talk with your healthcare provider or pharmacist.

What is Zyclara Cream?

-   -   Zyclara Cream is a skin use only (topical) medicine used to        treat external genital and perianal warts in people 12 years and        older.

Zyclara Cream does not work for everyone. Zyclara Cream may notcompletely cure your genital or perianal warts. New warts may developduring treatment with Zyclara Cream. It is not known if Zyclara Creamcan stop you from spreading genital or perianal warts to other people.For your own health and the health of others, it is important topractice safer sex. Talk to your healthcare provider about safer sexpractices.

Who should not use Zyclara Cream?

-   -   Zyclara Cream has not been studied in children under 12 years        old for external genital and perianal warts.

Before using Zyclara Cream, tell your healthcare provider:

-   -   about all your medical conditions, including if you        -   are pregnant or planning to become pregnant. It is not known            if Zyclara Cream can harm your unborn baby.        -   are breastfeeding. It is not known if Zyclara Cream passes            into your milk and if it can harm your baby.    -   about all the medicines you take including prescription and        non-prescription medicines, vitamins and herbal supplements.        Especially tell your healthcare provider if you have had other        treatments for genital or perianal warts. Zyclara Cream should        not be used until your skin has healed from other treatments.

How should I use Zyclara Cream?

-   -   Use Zyclara Cream exactly as prescribed by your healthcare        provider. Zyclara Cream is for skin use only. Do not take by        mouth and do not get Zyclara Cream in or near your eyes, lips or        nostrils. Do not use Zyclara Cream unless your healthcare        provider has taught you the right way to use it. Talk to your        healthcare provider if you have any questions.    -   Your healthcare provider will tell you where to apply Zyclara        Cream and how often and for how long to apply it for your        condition. Do not use Zyclara Cream longer than prescribed,        Using too much Zyclara Cream, or using it too often, or for too        long can increase your chances for having a severe skin reaction        or other side effect. Talk to your healthcare provider if        Zyclara Cream does not work for you.    -   Zyclara Cream is applied once a day. Zyclara Cream is usually        left on the skin for approximately 8 hours. Treatment should        continue until the warts are completely gone or for up to 8        weeks.

Applying Zyclara Cream

Zyclara Cream should be applied just before your bedtime.

-   -   Wash the area to be treated with mild soap and water. Allow the        area to dry.        -   Uncircumcised males treating warts under their penis            foreskin must pull their foreskin back and clean before            treatment and clean daily during the weeks of treatment.    -   Wash your hands    -   Open a new packet of Zyclara Cream just before use.    -   Apply a thin layer of Zyclara Cream only to the affected area or        areas to be treated. Do not use more Zyclara cream than is        needed to cover the treatment area. Do not use more than one        packet for each application.    -   Rub the cream in all the way to the affected area or areas.    -   Do not get Zyclara Cream in or around your eyes or mouth.    -   Do not get Zyclara in the anus when applying to perianal warts.    -   Female patients treating genital warts must be careful when        applying Zyclara Cream around the vaginal opening. Female        patients should take special care if applying the cream at the        opening of the vagina because local skin reactions on the        delicate moist surfaces can cause pain or swelling, and may        cause problems passing urine. Do not put Zyclara Cream in your        vagina.    -   Do not cover the treated area with an airtight bandage. Cotton        gauze dressings can be used. Cotton underwear can be worn after        applying Zyclara Cream to the genital or perianal area.    -   Safely throw away the open packet of Zyclara Cream so that        children and pets cannot get it. The open packet should be        thrown away even if all the Zyclara Cream was not completely        used.    -   After applying Zyclara Cream, wash your hands well.    -   Leave the cream on the affected area or areas for the time        prescribed by your healthcare provider. Do not bathe or get the        treated area wet before the right time has passed. Do not leave        Zyclara Cream on your skin longer than prescribed.    -   After about 8 hours, wash the treated area or areas with mild        soap and water. If you forget to apply Zyclara Cream, continue        on your regular schedule and do not make up the missed dose(s).    -   If you get Zyclara Cream in your mouth or in your eyes rinse        well with water right away.

What should I avoid while using Zyclara Cream?

-   -   Do not cover the treated site with bandages or other closed        dressings. Cotton gauze dressings are okay to use, if needed.        Cotton underwear can be worn after treating the genital or        perianal area.    -   Do not get Zyclara Cream in or near the eyes, lips or nostrils,    -   Do not put Zyclara Cream in your vagina or anus.    -   Do not use sunlamps or tanning beds, and avoid sunlight to the        treated area as much as possible during treatment with Zyclara        Cream.    -   Do not have sexual contact including genital, anal, or oral sex        when Zyclara Cream is on your genital or perianal skin. Zyclara        Cream may weaken condoms and vaginal diaphragms. This means they        may not work as well to prevent pregnancy. For your own health        and the health of others, it is important to practice safer sex.        Talk to your healthcare provider about safer sex practices.

What are the possible side effects of Zyclara Cream?Side effects withZyclara Cream may include skin reactions at the treatment site such as:

-   -   redness    -   swelling    -   a sore, blister, or ulcer    -   skin that becomes hard or thickened    -   skin peeling    -   scabbing and crusting    -   itching    -   burning    -   changes in skin color that do not always go away

During treatment and until the skin has healed, your skin in thetreatment area is likely to appear noticeably different from normalskin. Side effects, such as redness, scabbing, itching and burning arecommon at the site where Zyclara Cream is applied, and sometimes theside effects go outside of the area where Zyclara Cream was applied.Swelling, small open sores and drainage may also be experienced with useof Zyclara Cream. You may also experience itching, irritation or pain.Patients should be aware that new warts may develop during treatment, asZyclara Cream may not be a cure. Many people see reddening or swellingon or around the application site during the course of treatment. If youhave questions regarding treatment or local skin reactions, please talkwith your healthcare provider.

You have a higher chance for severe skin reactions if you use too muchZyclara Cream or use it the wrong way. Stop Zyclara Cream right away andcall your healthcare provider if you get any skin reactions that affectyour daily activities, or that do not go away, Sometimes, Zyclara Creammust be stopped for a while to allow your skin to heal, Talk to yourhealthcare provider if you have questions about your treatment or skinreactions.

Other side effects of Zyclara Cream include pain, fever, muscle aches,and may also include headache, back pain, joint aches, tiredness,flu-like symptoms, nausea, and diarrhea.

If the reactions seem excessive, if either skin breaks down or soresdevelop during the first week of treatment, if flu-like symptoms developor if you begin to not feel well at anytime, stop applying Zyclara Creamand contact your healthcare provider.

These are not all the side effects of Zyclara Cream. For moreinformation, ask your healthcare provider or pharmacist.

How do I store Zyclara Cream?

-   -   Store Zyclara Cream at 77° F. (25° C.). [59° to 86° F.; 15° to        30° C.] Do not freeze.    -   Safely throw away Zyclara Cream that is out of date or that you        do not need.    -   Keep Zyclara Cream and all medicines out of the reach of        children.

General information about Zyclara Cream

Medicines are sometimes prescribed for conditions that are not mentionedin patient information leaflets. Do not use Zyclara Cream for acondition for which it was not prescribed. Do not give Zyclara Cream toother people, even if they have the same symptoms you have.

This leaflet summarizes the most important information about ZyclaraCream. If you would like more information, talk with your healthcareprovider. You can ask your pharmacist or healthcare provider forinformation about Zyclara Cream that is written for the healthcareprovider. If you have other questions about Zyclara Cream, call1-800-328-0255.

What are the ingredients in Zyclara Cream?

Active Ingredient: imiquimod

Inactive ingredients: isostearic acid, cetyl alcohol, stearyl alcohol,white petrolatum, polysorbate 60, sorbiran monostearate, glycerin,xanthan gum, purified water, benzyl alcohol, methylparaben, andpropylparaben.

Manufactured by:

3M Health Care Limited, Loughborough LE11 IEP England

Distributed by:

Graceway Pharmaceuticals, LLC, Bristol, Tenn. 37620

The complete disclosures of the patents, patent documents, andpublications cited herein are incorporated by reference in theirentireties as if each were individually incorporated. In case ofconflict, the present specification, including definitions, shallcontrol. Various modifications and alterations to this invention willbecome apparent to those skilled in the art without departing from thescope and spirit of this invention. Illustrative embodiments andexamples are provided as examples only and are not intended to limit thescope of the present invention. The scope of the invention is limitedonly by the claims set forth as follows.

What is claimed is:
 1. A method for treating genital or perianal wartsin a subject 12 years old or older, the method comprising: applying animiquimod pharmaceutical cream formulated with 3.75% by weight imiquimodto the warts, once per day, each day, for up to 8 consecutive weeks oruntil clearance is observed, whichever occurs earlier, to treat thewarts.
 2. The method of claim 1, wherein the imiquimod pharmaceuticalcream further comprises a pharmaceutically acceptable vehicle.
 3. Themethod of claim 2, wherein the pharmaceutically acceptable vehiclecomprises a member selected from the group consisting of a fatty acid,an emollient, an emulsifier, a thickener, a preservative, a humectant,water, or a combination thereof.
 4. The method of claim 3, wherein thefatty acid is selected from the group consisting of isostearic acid,linoleic acid, oleic acid, super purified oleic acid, and a combinationthereof.
 5. The method of claim 3, wherein the fatty acid is isostearicacid.
 6. The method of claim 3, wherein the fatty acid is present in anamount of between about 5% to about 25% by weight.
 7. The method ofclaim 3, wherein the emollient is selected from the group consisting ofcetyl alcohol, stearyl alcohol, petrolatum, and a combination thereof.8. The method of claim 3, wherein the emollient is present in an amountof between about 5% to about 10% by weight.
 9. The method of claim 3,wherein the emulsifier is selected from the group consisting ofpolysorbate 60, sorbitan monostearate, and a combination thereof. 10.The method of claim 3, wherein the emulsifier is present in an amount ofbetween about 2% to about 6% by weight.
 11. The method of claim 3,wherein the preservative is selected from the group consisting ofmethylparaben, propylparaben, benzyl alcohol, and a combination thereof.12. The method of claim 3, wherein the humectant is glycerin.
 13. Themethod of claim 3, wherein the water is present in an amount of betweenabout 45% to about 85% by weight.
 14. The method of claim 2, wherein thepharmaceutically acceptable vehicle consists of isostearic acid, cetylalcohol, stearyl alcohol, white petrolatum, polysorbate 60, sorbitanmonostearate, glycerin, xanthan gum, water, benzyl alcohol,methylparaben, and propylparaben.
 15. The method of claim 1, wherein forevery 250 mg of the imiquimod pharmaceutical cream, the cream contains9.375 mg of imiquimod.
 16. The method of claim 1, wherein the imiquimodpharmaceutical cream is selected from the group of 3.75% imiquimodpharmaceutical creams listed in Example 29.